Pharmacologically active thiadiazole guanidine compounds

ABSTRACT

The compounds are substituted thioalkyl-, aminoalkyl- and oxyalkyl-guanidines which are inhibitors of histamine activity.

This is a division of application Ser. No. 764,921 filed Feb. 2, 1977,now U.S. Pat. No. 4,137,237, which is a division of application Ser. No.637,496 filed Dec. 4, 1975, now U.S. Pat. No. 4,022,797, which is adivision of application Ser. No. 450,957 filed Mar. 14, 1974, now U.S.Pat. No. 3,950,333, which is a continuation-in-part of Ser. No. 290,584filed Sept. 20, 1972, now abandoned, which is a continuation-in-part ofSer. No. 230,451 filed Feb. 29, 1972, now abandoned.

This invention relates to pharmacologically active compounds, topharmaceutical compositions comprising these compounds and to processesfor their preparation. The compounds of the invention can exist as theaddition salts but, for convenience, reference will be made throughoutthis specification to the parent compounds.

It has for long been postulated that many of the physiologically activesubstances within the animal body, in the course of their activity,combine with certain specific sites known as receptors. Histamine is acompound which is believed to act in such a way but, since the actionsof histamine fall into more than one type, it is believed that there ismore than one type of histamine receptor. The type of action ofhistamine which is blocked by drugs commonly called "antihistamines" (ofwhich mepyamine is a typical example) is believed to involve a receptorwhich has been designated by Ash and Schild (Brit. J. Pharmac. 1966,27,427) as H-1. The substances of the present invention aredistinguished by the fact that they act at histamine H-2 receptorswhich, as described by Black et al. (Nature, 1972, 236, 385), arehistamine receptors other than the H-1 receptor. Thus they are ofutility in inhibiting certain actions of histamine which are notinhibited by the above-mentioned "antihistamines". The substances ofthis invention may also be of utility as inhibitors of certain actionsof gastrin.

The compounds with which the present invention is concerned may berepresented by the following general formula; insofar as tautomerismaffects the compounds mentioned in this specification, the numbering ofthe nucleus has been modified accordingly: ##STR1## wherein A is suchthat there is formed together with the carbon atom shown an unsaturatedheterocyclic nucleus, which comprises at least one nitrogen and maycomprise a further hetero atom such as sulphur and oxygen, saidunsaturated heterocyclic nucleus being an imidazole, pyrazole,pyrimidine, pyrazine, pyridazine, thiazole, isothiazole, oxazole,isoxazole, triazole, thiadiazole, benzimidazole or5,6,7,8-tetrahydroimidazol[1,5-a]pyridine ring; X₁ is hydrogen, loweralkyl, hydroxyl, trifluoromethyl, benzyl, halogen, amino or ##STR2## X₂is hydrogen or when X₁ is lower alkyl, lower alkyl or halogen; k is 0 to2 and m is 2 or 3, provided that the sum of k and m is 3 or 4; Y isoxygen, sulphur, or NH; E is NR₂ ; R₁ is hydrogen, lower alkyl ordi-lower alkylamino-lower alkyl; and R₂ is hydrogen, nitro or cyano or apharmaceutically acceptable addition salt thereof. Y is preferablyoxygen or sulphur, most advantageously sulphur. Preferably A is suchthat the nitrogen atom is adjacent to the carbon atom shown and, morepreferably, such that it forms with the said carbon atom an imidazole,thiazole or isothiazole ring. Preferably, X₁ is hydrogen, methyl, bromo,amino or hydroxyl and X₂ is hydrogen. One group of preferred compoundswithin the present invention is that wherein Y is sulphur, k is 1, m is2 and R₁ is methyl. Specific compounds which are found to beparticularly useful are N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)-ethyl]guanidine,N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,N-cyano-N'-methyl-N"-[2-((4-bromo-5-imidazolyl)methylthio)ethyl]guanidine,N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]-guanidine andN-cyano-N'-methyl-N"-[2-(3-isothiazolylmethylthio)ethyl]guanidine.

The compounds with which the present invention is concerned wherein Y issulphur and k is 1 or 2 may be produced by processes which commence witha substance of the following general formula: ##STR3## wherein A, X₁ andX₂ have the same significance as in formula I except that X₁ may not be##STR4## but may additionally be (CH₂)_(k') Q; k' is 1 or 2 and Q ishydroxyl, halogen or methoxy. In the first stage of these processes, thecompound of formula II is reacted with an amino-mercaptan of thefollowing FORMULA III:

    HS--(CH.sub.2).sub.m --NH.sub.2

wherein m has the same significance as in formula I. When Q is halogen,this reaction may be carried out under strongly basic conditions, forexample in the presence of sodium ethoxide or sodium hydroxide. Sincethe substance of formula III is a primary amine it may be necessary toprotect the amino group, for example by a phthalimido group which maysubsequently be removed by acid hydrolysis or by hydrazinolysis. When Qis hydroxyl or halogen it is found that the reaction will take placeunder acidic conditions e.g. in the presence of a halogen acid such as48% aqueous hydrogen bromide, or a halogen acid in the presence ofglacial acetic acid. When Q is methoxy, the reaction will also takeplace in the presence of 48% hydrogen bromide.

When k is zero, the corresponding first stage of the reaction is betweena nucleus directly substituted with a thiol or a thione and, underacidic conditions, 3-aminopropanol or, under alkaline conditions, a3-halopyropylamine, the amino group being protected if required in thelatter case, e.g. by a phthalimido group which may be subsequentlyremoved by acid hydrolysis or by hydrazinolysis.

The product produced by these processes is of the following formula IV,and may, of course, be in the form of the acid addition salt: ##STR5##wherein X₁ has the same significance as in formula II and A, X₂, k and mhave the same significance as in formula I. The free base of formula IVmay be obtained from the acid addition salt by treatment with anappropriate base e.g. an alkali metal alkoxide such as sodium ethoxideor an inorganic base such as potassium carbonate.

In the case of compounds of formula I wherein Y is oxygen, the processfor their production commences with a compound of formula V (which mayitself be formed by treatment with thionyl halide of the correspondingalcohol resulting from the reaction of a haloalkyl heterocyclic compoundand the sodium salt of a diol) ##STR6## wherein A, X₁, X₂ and m have thesame significance as in formula I, k' is 1 or 2, k'+m is 3 or 4 and B ishalogen. This compound may be reacted with an alkali metal azide and theresulting product reduced, e.g. by hydrogenation over a platinum dioxidecatalyst, to yield an amine of formula VI in which k is 1 or 2 andwherein A, X₁, X₂ and m have the same significance as in formula I.##STR7##

The amines of formula VI in which k is zero are prepared by reacting ahalo-heterocycle under strongly basic conditions with1,3-dihydroxypropane, converting the resultant 3-hydroxypropoxy compoundwith thionyl chloride to the 3-chloropropoxy compound which on reactionwith sodium azide and reduction of the product yields the requiredamine.

The compounds of formula I wherein Y is NH are similarly formed from acompound of formula VII ##STR8## wherein the amino group in the alkylenechain may be protected when k is 1 or 2 and optionally the terminalamino group may also be protected and A, X₁, X₂, k and m have the samesignificance as in formula I, except that X₁ may not be ##STR9## but mayadditionally be (CH₂)_(k) Y(CH₂)_(m) NH₂.

The intermediates of formula VII are prepared by a process whichcommences with a substance of the following general formula: ##STR10##wherein A, X₁, X₂ and k have the same significance as in formula I,except that X₁ may not be ##STR11## but may additionally be (CH₂)_(k)-halo. In this process, a compound of formula VIII is reacted with adiamine of the following FORMULA IX:

    H.sub.2 N--(CH.sub.2).sub.m --NH.sub.2

wherein m has the same significance as in formula I. This reaction maybe carried out under strongly basic conditions, for example in thepresence of sodium ethoxide or sodium hydroxide or in an anhydroussolvent such as dimethylformamide in the presence of sodium hydride.

The compounds of formula I are prepared from the amines of formula IV,formula VI or formula VII by treatment thereof with an isothiourea offormula X ##STR12## wherein R₁ and R₂ have the same significance as informula I. The reaction is preferably carried out at elevatedtemperature in a solvent such as water, lower alkanol, acetonitrile orpyridine, or in the absence of a solvent when excess amine willpreferably be present.

Alternatively, the compounds of formula I wherein R₁ is lower alkyl andR₂ is cyano, are prepared by reacting a thiourea of formula XI:##STR13## wherein A, X₁, X₂, Y, k and m have the same significance as informula I and R₁ is lower alkyl with a heavy metal salt of cyanamidesuch as the lead, mercury or cadmium salt. This process may beconveniently carried out in a solvent such as acetonitrile ordimethylformamide. In a modification of this process the thiourea offormula XI is first reacted with a desulphurising agent such as heavymetal salt or oxide and then treated with cyanamide.

An advantageous method for the production of compounds of formula I inwhich R₂ is cyano is by the reaction of an amine of formulas IV, VI orVII with a cyanoimidodithiocarbonate or a cyanoimidocarbonate of formulaXII:

    (R.sub.3 Z).sub.2 C═N--CN

FORMULA XII

wherein R₃ is alkyl, preferably methyl, and Z is sulphur or oxygen,preferably sulphur, to give an N-cyanoisothiourea or N-cyanoisourea offormula XIII: ##STR14## wherein A, X₁, X₂, and m have the samesignificance as in formula I and Z and R₃ have the same significance asin formula XII. Subsequent reaction of the compounds of formula XIIIwith R₁ NH₂ leads to the production of cyanoguanidines of formula I.Both stages of this reaction may be carried out in a solvent such asethanol or isopropyl alcohol. In a modification of this method, thecompound of formula XII, which in the preferred case isdimethyl-N-cyanoimidodithiocarbonate, may be reacted sequentially withan amine of formulas IV, VI or VII and with R₁ NH₂ without isolation ofthe intermediate compound of formula XIII.

In an alternative method for the production of those compounds offormula I wherein R₁ is hydrogen and R₂ is cyano, an amine of formulasIV, VI or VII is reacted with a metal salt of dicyanamide of formulaMN(CN)₂ wherein M is a metal, e.g. an alkali metal such as sodium, in anappropriate solvent and in the presence of an equivalent amount of astrong acid.

As stated above, the compounds represented by formula I have been foundto have pharmacological activity in the animal body as antagonists tocertain actions of histamine which are not blocked by "antihistamines"such as mepyramine. For example, they have been found to inhibitselectively the histamine-stimulated secretion of gastric acid from theperfused stomachs of rats anaesthetised with urethane, at doses of from0.5 to 256 micromoles per kilogram intravenously. Similarly, the actionof these compounds is demonstrated by their antagonism to the effects ofhistamine or other tissues which, according to the above-mentioned paperof Ash & Schild, are not H-1 receptors. Examples of such tissues areperfused isolated guinea-pig heart, isolated guinea-pig right atrium andisolated rat uterus. The compounds of the invention have also been foundto inhibit the secretion of gastric acid stimulated by pentagastrin orby food. In addition to the above the compounds of the invention alsoshow antiinflammatory activity in conventional tests such as the rat pawoedema test at doses of about 500 micromoles/kg. subcutaneously.

The level of activity found for the compositions comprising thecompounds of the present invention is illustrated by the effective doserange in the anaesthetized rat, as mentioned above of from 0.5 to 256micromoles per kilogram, given intravenously.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 gm. If a liquid carrier is used,the preparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule, or an aqueous ornonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effectiveamount to inhibit histamine activity. The route of administration may beorally or parenterally.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg. to about 250 mg. most preferably from about100 mg. to about 200 mg.

The active ingredient will preferably be administered in equal doses oneto four times per day. The daily dosage regimen will preferably be fromabout 150 mg. to about 1000 mg., most preferably from about 400 mg. toabout 800 mg.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids.

Other pharmacologically active compounds may in certain cases beincluded in the composition. Advantageously the composition will be madeup in a dosage unit form appropriate to the desired mode ofadministration, for example as a tablet, capsule, injectable solutionor, when used as an anti-inflammatory agent, as a cream for topicaladministration.

The invention is illustrated but in no way limited by the followingexamples.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a five membered unsaturated heterocyclic ringhaving two nitrogen atoms and three carbon atoms, said unsaturatedheterocyclic ring being imidazole or pyrazole, and Y is oxygen orsulphur (sulphur is preferred) are exemplified by the followingexamples.

EXAMPLE 1 2-(4-Imidazolylmethylthio)ethylguanidine sulphate

i. a. A solution of 4(5)-hydroxymethylimidazole hydrochloride (67 g.)and cysteamine hydrochloride (56.8 g.) in aqueous hydrobomic acid (1liter, 48%) was heated under reflux overnight. After cooling, thesolution was evaporated to dryness and the residual solid washed withethanol/ether to give 4(5)-[(2-aminoethyl)thiomethyl]imidazoledihydrobromide (156 g.), m.p. 178°-179°.

b. Phthalimidoethanethiol (2 g.) was added portionwise with stirring toa solution of sodium ethoxide (prepared from 0.23 g. of sodium) inethanol (20 ml.) at 0° under a nitrogen atmosphere. After stirring at 0°for a further 2.5 hours, the resulting yellow solution was cooled withan ice-salt bath and a solution of 4(5)-chloromethylimidazolehydrochloride (0.76 g.) in ethanol (5 ml.) was added dropwise over 10minutes. After addition the mixture was stirred at room temperatureovernight, then acidified with ethanolic hydrogen chloride andevaporated to dryness. Addition of water precipitated unreactedphthalimidoethanethiol (0.6 g.) which was removed by filtration. Thefiltrate was concentrated and basified with aqueous sodium bicarbonatesolution to furnish a white precipitate which, on recrystallisation fromaqueous ethanol, gave 4-(5)-[(2-phthalimidoethyl)thiomethyl]-imidazole(0.75 g.) m.p. 136°-137°. A stirred mixture of this phthalimidoderivative (0.62 g.) in aqueous hydrobromic acid (40 ml. 18%) was heatedunder reflux overnight. After cooling to 0°, the resulting clearsolution was filtered and the filtrate evaporated to dryness.Recrystallisation of the residue from ethanol gave4-(5)-[(2-aminoethyl)thiomethyl]-imidazole dihydrobromide (0.52 g.),m.p. 178°-179°.

c. A suspension of cysteamine hydrochloride (118.8 g.) in ethanol (200ml., dried over molecular sieves) was added portionwise at 0° to asolution of sodium ethoxide (prepared from 48 g. of sodium) in ethanol(1 liter) under a nitrogen atmosphere. After stirring at 0°, for afurther 2 hours, a solution of 4(5)-chloromethylimidazole hydrochloride(80 g.) in ethanol (400 ml.) was added dropwise over 45 minutes whilethe temperature was maintained at -1°±2°. After addition, the mixturewas stirred at room temperature overnight, filtered, and the filtrateacidified with concentrated hydrochloric acid. The solution was thenevaporated to dryness, the residue dissolved in ethanol (1 liter) and asolution of excess picric acid in hot ethanol added. The resulting crudepicrate was dissolved in water (2.7 liters) and, after decantation froman insoluble oil, the solution was left to cool to give4(5)-[(2-aminoethyl)thiomethyl]imidazole dipicrate, m.p. 194°-195°.Treatment of this picrate with aqueous hydrobromic acid followed byextraction with toluene gave the dihydrobromide, m.p. 178°-179°, afterevaporation to dryness and recrystallisation of the crude residue fromethanol. (ii) A solution of 4(5)-[(2-aminoethyl)thiomethyl]imidazoledihydrobromide (10 g.) in water (25 ml.) was basified to pH 11 by theaddition of a solution of potassium carbonate (8.7 g.) in water (25ml.). The resulting solution was evaporated to dryness, extracted withisopropyl alcohol and the final traces of water removed by azeotropingwith isopropyl alcohol. The residual amine was extracted from theinorganic material with isopropyl alcohol, the extracts concentrated todryness to give 4-[(2-aminoethyl)thiomethyl]imidazole.

A solution of 4-[(2-aminoethyl)thiomethyl]imidazole (5.8 g.) andS-methylisothiouronium sulphate (4.8 g.) in water (50 ml.) was heatedunder reflux for 3 hours. Following concentration to low bulk andacidification with dilute sulphuric acid, ethanol was added. The productobtained was recrystallised from aqueous methanol to give2-(4-imidazolylmethylthio)ethylguanidine sulphate (5.2 g.), m.p.211°-213°. (Found: C, 28.1; H, 5.1; N, 23.3; S, 21.3; C₇ H₁₃ N₅ S. H₂SO₄ requires: C, 28.3; H, 5.1; N, 23.6; S, 21.6).

EXAMPLE 2

i. a. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride(30.0 g.) and cysteamine hydrochloride (23.0 g.) in acetic acid (200ml.) was heated under reflux for 10 hours. Following cooling to 15°-20°,the solid which crystallised was collected and washed with isopropylalcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazoledihydrochloride (45.5 g.), m.p. 189°-192°.

b. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueoushydrochloric acid (450 ml.) was heated under reflux for 17 hours.Concentration followed by re-evaporation with water afforded a residuewhich was dissolved in isopropyl alcohol, concentrated to low bulk andcooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazoledihydrochloride (40.6 g.), m.p. 185°-191°.

c. A mixture of 4-hydroxymethyl-5-methylimidazole hydrochloride (15.0g.), cysteamine hydrochloride (11.5 g.) and a solution of hydrogenbromide in acetic acid (48%, 225 ml.) was heated under reflux for 7hours. Cooling afforded 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazoledihydrobromide (21.6 g.), m.p. 208°-211°.

ii. Potassium carbonate (7.75 g.) was added to a solution of4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g.)in water (120 ml.). The solution was stored at room temperature for 15minutes, then evaporated to dryness, extracted with isopropyl alcoholand the extracts are concentrated to dryness to give4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole.

A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (1.7 g.)and S-methyl-N-nitroisothiourea (1.45 g.) in methanol (35 ml.) washeated at 50°-60° for 2.5 hours and then set aside at room temperaturefor 48 hours. The crystalline product was filtered off andrecrystallized from methanol to giveN-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-nitroguanidine, m.p.184°-186°. (Found: C, 37.5; H, 5.7; N, 32.5; S, 12.5. C₈ H₁₄ N₆ O₂ Srequires: C, 37.2; H, 5.5; N, 32.5; S, 12.4). (iii) Similarly reactionof N,S-dimethyl-N'-nitroisothiourea (1.6 g.) (m.p. 146°-147°, formed bythe treatment of N,S-dimethylisothiouronium methosulphate with fumingnitric acid and concentrated sulphuric acid at -20°) with4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole by the above procedurefollowed by chromatographic purification on a column of silica gel withacetone as eluant, gives N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-nitroguanidine (1.23 g.), m.p.112°-114°. (Found: C, 39.5; H, 6.2; N, 30.6; S, 11.5 C₉ H₁₆ N₆ O₂ Srequires: C, 39.7; H, 5.9; N, 30.9; S, 11.8.

EXAMPLE 3

a. A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (17.0g.) and N-cyano-N',S-dimethylisothiourea (11.2 g.) in acetonitrile (500ml.) was heated under reflux for 24 hours. Following concentration, theresidue was chromatographed on a column of silica gel with acetonitrileas eluant and the product obtained was finally recrystallised fromacetonitrile-ether to yieldN-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,m.p. 141°-2°. (Found: C, 47.2; H, 6.4; N, 33.4; S, 12.4. C₁₀ H₁₆ N₆ Srequires: C, 47.6; H, 6.4; N, 33.3; N, 12.7).

b. i. Potassium carbonate (7.75 g.) was added to a solution of4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g.)in water (120 ml.). The solution was stirred at room temperature for 15minutes and methyl isothiocyanate (5.15 g.) was added. After heatingunder reflux for 30 minutes, the solution was slowly cooled to 5°. Theproduct (13.1 g.) was collected and recrystallized from water to giveN-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea, m.p.150°-152°.

ii. Lead cyanamide (3.0 g.) was added to a solution ofN-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethylthiourea (2.44g.) in acetonitrile (50 ml.). Dimethylformamide (20 ml.) was addedsubsequently and the suspension was heated under reflux, with stirringfor 24 hours. Filtration, followed by concentration under reducedpressure and purification of the product by chromatography on a columnof silica gel with acetonitrile as eluant and recrystallisation from thesame solvent affordedN-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine,methylthio)ethyl]guanidine, m.p. 139°-141°. (Found: C, 47.3; H, 6.6; N,33.4; S, 12.6. C₁₀ N₁₆ N₆ S requires: C, 47.6; H, 6.4; N, 33.3; S,12.7).

c. i. A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (23.4g.) in ethanol was added slowly to a solution ofdimethyl-N-cyanoimidodithiocarbonate (20.0 g.) in ethanol with stirringat room temperature. The mixture was set aside overnight at roomtemperature. Filtration affordedN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(10.0 g.), m.p. 148°-150°. The filtrate was concentrated under reducedpressure and the mixture was triturated with cold water and the solidobtained, filtered off and recrystallised twice from isopropylalcohol/ether to yield further product (27 g.), m.p. 148°-150°. (Found:C, 44.4; H, 5.6; N, 26.0; S, 24.3 C₁₀ H₁₄ N₅ S₂ requires: C, 44.6; H,5.6; N, 26.0; S, 23.8).

ii. A solution of methylamine in ethanol (33%, 75 ml.) was added to asolution ofN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(10.1 g.) in ethanol (30 ml.). The reaction mixture was set aside atroom temperature for 2.5 hours. Following concentration under reducedpressure, the residue was recrystallized twice from isopropylalcohol/petroleum ether, affordingN-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine(8.6 g.), m.p. 141°-143°. (Found: C, 47.5; H, 6.3; N, 33.2; S, 12.9. C₁₀H₁₆ N 6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).

d. A solution of 4-methyl-5-[(2-aminoethyl)thiomethylimidazole (1.93 g.)and dimethyl-N-cyanoimidodithiocarbonate (1.65 g.) in ethanol (33 ml.)was set aside overnight at room temperature. Ethanolic methylamine (33%,22 ml.) was added and the solution was then set aside for 4 hours.Concentration and recrystallization from isopropyl alcoholether yieldedN-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine(2.0 g.), m.p. 139°-140°. (Found: C, 47.5; H, 6.5; N, 33.3; S, 12.7. C₁₀H₁₆ N₆ S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).

c. WhenN-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidineis treated with concentrated hydrochloric acid at 100° for 4 hours, theproduct which is recrystallised from ethanol-ether isN-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinedihydrochloride, m.p. 204°-206°. (Found: C, 35.8; H, 6.5; N, 22.7; S,10.8; Cl, 23.7. C₉ H₁₇ N₅ S.2HCl requires: C, 36.8; H, 6.4; N, 23.3; S,10.7; Cl, 23.6).

EXAMPLE 4N-Cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

a. Anhydrous ethylamine (9.0 g.) was added to a solution ofN-cyano-N-'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(Example 3(c). 5.0 g.) in ethanol. The solution was heated under refluxfor 8 hours and concentrated under reduced pressure. The residue wasdissolved in isopropyl alcohol, filtered, and diluted with water. Thewhite solid obtained was recrystallised from isopropyl alcohol-ether toyieldN-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine.m.p. 118°-120°. (Found: C, 49.6; H, 6.8; N, 31.2 S. 11.7. C₁₁ H₁₈ N₆ Srequires: C, 49.6; H, 6.8; N, 31.6; S, 12.0).

b. i. A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (6.9g.) and ethyl isothiocyanate (3.84 g.) in ethanol was heated underreflux for 2 hours. Concentration followed by recrystallisation of theresidue from aqeuous ethanol gaveN-ethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)thiourea(9.0 g.), m.p.140°-141°. (Found: C, 46.5; H, 7.1; N, 21.7; S, 25.1, C₁₀ H₁₈ N₄ S₂requires: C, 46.5; H, 7.0; N, 21.7; S, 24.8).

ii. Reaction of the thiourea with excess lead cyanamide by a proceduresimilar to that described in Example 3(b) affordedN-cyano-N'-ethyl-N"-[2((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,comparable with that described in Example 4(a).

EXAMPLE 5N-Cyano-N'-[2-((4-methyl-5-imidazoyl)methylthio)ethyl)guanidine

A solution ofN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]S-methylisothiourea(2.69 g.) in saturated ammoniacal ethanol (100 ml.) was heated in apressure vessel for 16 hours at 95°. Following concentration, theresidue was chromatographed on a column of silica gel with ethyl acetateas eluant and finally recrystallised from acetonitrile to giveN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (0.9g.) m.p. 125°-127°. (Found: C, 45.2; H, 5.9; N, 35.1; S, 13.3, C₉ H₁₄ N₆S requires: C, 45.4; H, 5.9; N, 35.3; S, 13.5).

EXAMPLE 6N-[2-((4-Bromo-5-imidazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

The sequential reaction of dimethyl-N-cyanoimidodithiocarbonate (0.99g.) with 4-bromo-5-[(2-aminoethyl)-thiomethyl]imidazole (1.6 g.),prepared by the procedures of Example 1, and excess methylamine by theprocedure described in Example 3(d) affordedN-[2-((4-bromo-5-imidazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine(1.45 g.), m.p. 144°-146° (from nitromethane). (Found: C, 34.3; H, 4.2;N, 26.7; S, 10.1, C₉ H₁₃ BrN₆ S requires: C, 34.1; H, 4.1; N, 26.5; S,10.2).

EXAMPLE 7N-Cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-N"-methylguanidine

A solution of 4(5)-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide(10 g.) in water (25 ml.) was basified to pH 11 by the addition of asolution of potassium carbonate (8.7 g.) in water (25 ml.). Theresulting solution was evaporated to dryness, extracted with isopropylalcohol and the final traces of water removed by azeotroping withisopropyl alcohol. The residual amine was extracted from the inorganicmaterial with isopropyl alcohol, the extracts concentrated to about 70ml and a solution of methyl isothiocyanate (2.3 g.) in isopropyl alcohol(5 ml.) added. The reaction mixture was then heated under reflux for 1.5hours and, after cooling, evaporated to dryness. The residual oil wasdissolved in acetone, the solution filtered to remove traces ofinorganic material, and the filtrate concentrated to giveN-methyl-N"-[2-(4-imidazolylmethylthio)ethyl]thiourea (4.1 g.) m.p.96°-99°. A sample, recrystallised from acetone, had m.p. 98°-99°.

Lead cyanamide (24.7 g) was added to a solution ofN-methyl-N'-[2-(4-imidazolylmethylthio)ethyl]thiourea (11.5 g.) inacetonitrile (250 ml.) containing dimethylformamide. The stirredsuspension was heated under reflux for 48 hours. Filtration followed byconcentration under reduced pressure and purification of the product ona column of silica gel with ethyl acetateisopropyl alcohol (2.1) aseluant gaveN-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-N"-methylguanidine (3.7 g),m.p. 138°-140° (from acetonitrile). (Found: C, 45.7; H, 5.9; N, 35.5; S,13.5, C₉ H₁₄ N₆ S requires: C, 45.4; H, 5.9 N, 35.3; S, 13.5).

EXAMPLE 8N-Cyano-N'-methyl-N"-[3-((4-methyl-5-imidazolyl)methylthio)propyl]guanidine

i. A solution of homocysteamine hydrochloride (22.0 g.) and4-hydroxymethyl-5-methylimidazole hydrochloride (25.6 g.) in aqueoushydrobromic acid (500 ml.) was heated under reflux for 1 hour.Concentration under reduced pressure, followed by recrystallisation frommethanol-isopropyl alcohol afforded4-methyl-5-[(3-aminopropyl)thiomethyl]imidazole dihydrobromide (24.5g.), m.p. 200.5°-202.5°.

ii. The reaction of 4-methyl-5-](3-aminopropyl)thiomethyl]imidazole(from the dihydrobromide, 20.0 g.) with methyl isothiocyanate (4.5 g.)in isopropyl alcohol affordedN-methyl-N'-[3-((4-methyl-5-imidazolyl)methylthio)propyl]thiourea. m.p.104°-105.5° (from methyl ethyl ketone). (Found: C, 46.6; H, 7.0; N,21.7; S, 24.6, C₁₀ H₁₈ N₄ S₂ requires: C, 46.5; H, 7.0; N, 21.7; S,24.8).

iii. The reaction ofN-methyl-N'-[3-((4-methyl-5-imidazolyl)methylthio)propyl]thiourea (5.9g.) with lead cyanamide (17.5 g.) by a procedure similar to thatdescribed in Example 3(b) affordedN-cyano-N'-methyl-N"-[3-((4-methyl-5-imidazolyl)methylthio)propyl]-guanidine(0.91 g.) m.p. 156°-158°, following chromatography on silica gel withsuccessive elution by chloroformethyl acetate (1:1), ethyl acetate andethyl acetate isopropyl alcohol (5:1) and final recrystallisation fromisopropyl alcohol-ether. (Found: C, 49.5; H, b 7.0; S, 12.0. C₁₁ H₁₈ N₆S requires: C, 49.6; H, 6.8; S. 12.0).

EXAMPLE 9N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-propylguanidine

A solution ofN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(2.69 g.) and n-propylamine (1.1 g.) in ethanol (50 ml.) was heatedunder reflux for 6 hours. Concentration, followed by chromatographicpurification on a column of silica gel with ethyl acetate-isopropylalcohol (4:1) as eluant and final recrystallisation from aqueousisopropyl alcohol affordedN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl[N"-propylguanidine(2.0 g.) m.p. 108°-110°. (Found: C, 51.4; N, 30.0; S, 11.4. C₁₂ H₂₀ N₆ Srequires: C, 51.4; H, 7.2; N, 30.0; S, 11.4).

EXAMPLE 10

By the procedure of Example 1, the following amines were prepared:

2-[(2-aminoethyl)thiomethyl]imidazole

1-methyl-2-](2-aminoethyl)thiomethyl]imidazole

2-methyl-4-[(2-aminoethyl)thiomethyl]imidazole

1-methyl-4-](2-aminoethyl)thiomethyl]imidazole

1,5-dimethyl-2-](2-aminoethyl)thiomethyl]imidazole

5-chloro-1-methyl-2-](2-aminoethyl)thiomethyl]-imidazole.

The above amines were reacted with dimethyl-N-cyanoimidodithiocarbonateand then with methylamine by the procedure of Example 3(c) to give thefollowing products, respectively:

N-cyano-N'-[2-(2-imidazolylmethylthio)ethyl]-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((1-methyl-2-imidazolyl)-methylthio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((2-methyl-4-imidazolyl)-methylthio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2((1-methyl-4-imidazolyl)methylthio)ethyl]guanidine

N-cyano-N'-[2-((1,5-dimethyl-2-imidazolyl)methylthio)-ethyl]-N"-methylguanidine

N-[2-((5-chloro-1-methyl-2-imidazolyl)methylthio)-ethyl]-N'-cyano-N"-methylguanidine.

EXAMPLE 11N-Cyano-N'-methyl-N"-[2-(4-trifluoromethyl-5-imidazolylmethylthio)ethyl]guanidine

A mixture of ethyl 2-chloro-4,4,4-trifluoroacetate (65.7 g.), distilledformamide (135 g.) and water (11 ml.) was heated at 128°-130° for 1.5hours. After cooling, an equal volume of ice-cold water was added togive 4-trifluoromethyl-5-carbethoxyimidazole, m.p. 184°-186° (fromaqueous methanol).

Reduction of the ester (9.4 g.) with lithium aluminium hydride (2.4 g.)in tetrahydrofuran gave 5-hydroxymethyl-4-trifluoromethylimidazole,isolated as its picrate, m.p. 13.5°-137.5° (from aqueous isopropylalcohol).

The picrate (5.3 g.) was dissolved in 48% aqueous hydrobromic acid andextracted with toluene to remove picric acid. Cysteamine hydrochloride(1.52 g.) was added to the aqueous phase and the acidic solution heatedunder reflux for 12 hours. Concentration and trituration of the residuewith ethanol-ether gave4-trifluoromethyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide(3.2 g.) m.p. 179°-182°. Basification followed by treatment withdimethyl-N-cyanoimidodithiocarbonate and then with methylamine by theprocedure of Example 3(c) gives the title compound.

EXAMPLE 12 N-Cyano-N"-[2-(4-imidazolylmethoxy)ethyl]-N"-methylguanidine

A stirred suspension of 4-(2-chloroethoxymethyl(imidazole hydrochloride(14.7 g.) and sodium azide (9.8 g.) in dry dimethylformamide (103 ml.)was maintained at 95° for 5 hours and then set aside overnight at roomtemperature. Following dilution with water and filtration, the filtratewas concentrated and the residue purified by chromatography on a drycolumn of alumina using ethanol. The produce was basified with potassiumcarbonate (6.5 g.) in water (3 ml.) and the anhydrous residue wasextracted with isopropyl alcohol (3×50 ml.). Concentration of theextracts afforded 4-(2-azidoethoxymethyl)imidazole (7.2 g.)Hydrogenation of the azido compound (7.2 g.) in isopropyl alcohol (142ml.) over platinum oxide catalyst (3.0 g.) gave4-(2-aminoethoxymethyl)imidazole (6.48 g.). A sample of the monopicratemonohydrochloride had m.p. 139°-140° (Found: C, 35.4; H, 3.8; N, 20.5;Cl, 8.8. C₁₂ H₁₅ ClN₆ O₈ requires: C, 35.4; H, 3.7; N, 20.7; Cl. 8.7).

Treatment of the above prepared amine withdimethyl-N-cyanoimidodithiocarbonate and then with methylamine by theprocedure of Example 3(c) gives the title compound.

EXAMPLE 13

Sulphuryl chloride (286 g.) was added dropwise to a solution of ethyl3-oxopentanoate (300 g.) in chloroform (250 ml.) at 10°-15°. Followingaddition the mixture was stirred overnight at room temperature, heatedunder reflux for 0.5 hour and cooled. After washing with water, sodiumbicarbonate and water, the solution was dried (sodium sulphate),concentrated, and fractionated to yield ethyl 2-chloro-3-oxopentanoate,b.p. 94°-96°/14 mm.

A mixture of ethyl 2-chloro-3-oxopentanoate (178 g.), freshly distilledformamide (450 g.) and water (38 ml.) was heated at 140°-148° and thencooled and added to dilute hydrochloric acid. After decanting frominsoluble material, the solution was basified with ammonium hydroxide togive a solid which, following recrystallization from aqueous ethanol andethanol-ethyl acetate, yielded 4-ethyl-5-carbethoxyimidazole (29 g.)m.p. 170°-172°. This ester (14.0 g.) was reduced with lithium aluminiumhydride (4.6 g.) in tetrahydrofuran and then heated with hydrogenchloride to give 4-ethyl-5-hydroxymethylimidazole hydrochloride (10.6g.) m.p. 141°-143° (from isopropyl alcoholether). This 5-hydroxymethylcompound is converted to 4-ethyl-5-[(2-aminoethyl)thiomethyl]imidazoleby the procedure of Example 2.

Using the above prepared amine intermediate in the procedure of Example3 givesN-cyano-N'-methyl-N"-[2-((4-ethyl-5-imidazolyl)methylthio)ethyl]guanidine..

Hydrolysis of the latter compound with concentrated hydrochloric acid bythe method of Example 3(e) givesN-methyl-N'-[2-((4-ethyl-5-imidazolyl)methylthio)ethyl]-guanidinedihydrochloride.

EXAMPLE 14

A solution of sodium nitrite (43.8 g.) in water 92 ml.) was addeddropwise, with stirring, to a solution of ethyl isobutyrylacetate (100.3g.) in acetic acid (80 ml.) at 0°. After stirring at 0° for 30 minutesthen at room temperature for 3 hours, water (100 ml.) was added and themixture extracted with ether. The extracts were washed with water,saturated sodium bicarbonate solution and water. After drying (CaSO₄),the solution was evaporated to give ethyl2-oximino-4-methyl-3-oxopentanoate (112 g.) as a crude oil.

A solution of this oximinoketone (219 g.) in methanol (280 ml.) wasadded to a suspension of pre-reduced palladised charcoal (10 g., 10%) inethanol (1 liter) and saturated ethanolic hydrogen chloride (512 ml.)and the mixture hydrogenated at room temperature and pressure until thetheoretical amount of hydrogen was taken up. The mixture was filtered,the filtrate concentrated and ethyl acetate added to give ethyl2-amino-4-methyl-3-oxopentanoate hydrochloride (230.6 g.) m.p. 129°-131°(dec.). This aminoketone (50.5 g.) was dissolved in redistilledformamide (180 ml.) and the solution heated at 120° for 2 hours, 130°for 1 hour, and finally at 140° for 2 hours. After cooling, the mixturewas filtered and the crystalline product washed with water to give ethyl4-isopropyl-5-carbethoxy-imidazole (22 g.) m.p. 177°-178°.

This ester (108 g.) was placed in a soxhlet and reduced with lithiumaluminum hydride (34.5 g.) in tetrahydrofuran to give4-hydroxymethyl-5-isopropylimidazole (62.3 g.) m.p. 121°-123°. By theprocedure of Example 2, this 4-hydroxymethyl compound was converted tothe 4-[(2-aminoethyl)thiomethyl]intermediate.

Using the above prepared amine intermediate in the procedure of Example2(iii) gives N-methyl-N'-[2-((5-isopropyl-b4imidazolyl)methylthio)ethyl]-N"-nitroguanidine.

EXAMPLE 15N-[2-((4-Benzyl-5-imidazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

Reaction of ethyl 3-oxo-4-phenylbutyrate (10.3 g.) with sodium nitritefollowed by reduction of the crude ethyl2-oximino-3-oxo-4-phenylbutyrate (10.8 g.) by hydrogenation gave ethyl2-amino-3-oxo-4-phenylbutyrate hydrochloride (8.5 g.) m.p. 150°-153° C.An analytical sample, recrystallised from ethanol/ethyl acetate, hadm.p. 154°-155°.

Reaction of this aminoketone (160 g.) with formamide (480 ml.) byheating at 120°-140° over five hours gave 4-benzyl-5-carbethoxyimidazole(75 g.) m.p. 168.5°-169.5°. Reduction of this ester (30 g.) with lithiumaluminum hydride (6.4 g.) in tetrahydrofuran (600 ml.), followed byaddition of water, filtration and acidification of the filtrate withethanolic hydrogen chloride, gave 4-benzyl-5-hydroxymethylimidazolehydrochloride (22.9 g.), m.p. 149°-151°, after concentration andaddition of ethyl acetate.

By the procedure of Example 1, the above prepared hydroxymethyl compoundis converted to 5-[(2-aminoethyl)thiomethyl]-4-benzylimidazole.

Using the above prepared amine as the starting material in the procedureof Example 3(a) givesN-[2-((4-benzyl-5-imidazolyl)methylthio)ethyl]-N'cyano-N"-methylguanidine.

EXAMPLE 16N-Cyano-N'-(2-dimethylaminoethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]quanidine

By the procedure of Example 4, 2-(dimethylamino)ethylamine is reactedwithN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothioureato give the title compound.

EXAMPLE 17

A solution of 4(5)-(2-chloroethyl)imidazole hydrochloride (13.6 g.) andcysteamine hydrochloride (9.3 g.) in distilled water (100 ml.) was addedover 30 minutes to a stirred solution of potassium hydroxide (15.8 g,85%) in water (40 ml.) at room temperature under a nitrogen atmosphere.After addition the solution was heated for 4 hours at 50°. From time totime it was necessary to add a few drops of potassium hydroxide solutionto prevent the pH of the reaction mixture falling below 11. The reactionmixture was then acidified with 2N hydrochloric acid, evaported todryness under reduced pressure and the final traces of water removed byazeotroping with n-propanol. The residue was extracted several timeswith isopropyl alcohol and the combined extracts added to a hot solutionof picric acid in isopropyl alcohol. On cooling, this gave4(5)-[2-(2-aminoethyl)thioethyl]imidazole dipicrate (42.3 g.) m.p.225°-226°.

This dipicrate was converted to the dihydrochloride by addition ofconcentrated hydrochloric acid (200 ml.) followed by extraction withtoluene (5×50 ml.). The aqueous solution was evaporated to dryness, theresidue dissolved in water and the solution basified by the addition ofaqueous potassium carbonate solution. This mixture was then evaporatedto dryness and the residue extracted with n-propanol to give the crudebase of 4(5)-[2-(2-aminoethyl)thioethyl]imidazole on removal of then-propanol.

Using the above prepared amine as the starting material in the procedureof Example 3 givesN-cyano-N'-[2-(2-(4-imidazolyl)ethyl)thioethyl]-N"-methylguanidine.

Using the above prepared amine as the starting material in the procedureof Example 2(iii) givesN-methyl-N'-[2-(2-(4-imidazolyl)ethyl)thioethyl]-N"-nitroguanidine.

EXAMPLE 18 N-Cyano-N'-[2-(4-imidazolylmethylthio)ethyl]guanidine

4-((2-Aminoethyl)thiomethyl)imidazole is reacted withdimethyl-N-cyanoimidodithiocarbonate according to the procedure ofExample 3(c)(i) and the resultantN-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-S-methylisothiourea treatedwith ammonical ethanol according to the procedure of Example 5 to givethe title compound.

EXAMPLE 19

The reaction of 4,5-dihydroxymethylimidazole hydrochloride (1.6 g.) withcysteamine hydrochloride (2.2 g.) by the procedure described in Example1(i)(a) afforded 4,5-bis-((2-aminoethyl)thiomethyl)imidazoletrihydrobromide (3.8 g.), m.p. 223°-236° C.

Using the above prepared amine as starting material in the procedure ofExample 3 gives4,5-bis-[2-(N-cyano-N'-methylguanidino)ethylthiomethyl]imidazole.Hydrolysis of this compound by the procedure of Example 3(e) gives4,5-bis-[2-(N-methylguanidino)ethylthiomethyl]imidazoletrihydrochloride.

EXAMPLE 20 N-Cyano-N'[3-(2-imidazolylthio)propyl-N"-methylguanidine

A solution of 2-mercaptoimidazole (2 g.) and 3-aminopropanol (1.14 ml.)in hydrobromic acid (48%, 25 ml.) was heated under reflux for 25 hours.The reaction mixture was evaporated to dryness and the oily residualsolid recrystallized twice from ethanol/ether to give2(3-aminopropylthio)imidazole dihydrobromide (3.55 g.), m.p. 160°-162°.

The above prepared dihydrobromide salt is converted to the free base andreacted with N-cyano-N',S-dimethylisothiourea by the procedure ofExample 3(a) to give the title compound.

EXAMPLE 21N[2-((4-Dimethyl-2-imidazolyl)methylthio)ethyl]-N'-nitroguanidine

The reaction of 1,4-dimethylimidazole (5.65 g.) with n-butyl lithiumfollowed by treatment with formaldehyde (according to the methoddescribed for the preparation of3-hydroxymethyl-5,6,7,8-tetrahydroimidazol[1,5-a]pyridine in Example243) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71) g.) m.p.125°-126° (ethyl acetate-petroleum ether).

The reaction of 1,4-dimethyl-2-hydroxymethylimidazole (2.5 g.) withcysteamine hydrochloride (2.5 g.) in aqueous hydrobromic acid by themethod described in Example 1(i)(a) gave1,4-dimethyl-2-](2-aminoethyl)thiomethyl]imidazole dihydrobromide (6.2g.) m.p. 161°-162° (from isopropyl alcoholmethanol).

Using the above prepared amine dihydrobromide as the starting materialin the procedure of Example 2(ii) gives the title compound.

EXAMPLE 22 N-Cyano-N'-[3-(4-imidazolylmethoxy)propyl]-N"-methylguanidine

Sodium (13.5 g.) was added over 3 hours to propane-1,3-diol (450 ml.)under nitrogen at 70° with stirring. This solution was added over 20minutes to a stirred solution of 4-chloromethylimidazole hydrochloride(50.0 g.) under nitrogen at 40°-60°. Subsequent heating at 60°-65° for 3hours followed by overnight cooling, filtration and concentration gave4-(3-hydroxypropoxy)methylimidazole. Subsequent reaction with thionylchloride gave 4(3-chloropropoxy)methylimidazole hydrochloride (38.3 g.).

The reaction of this chloride (36.2 g.) with sodium azide (22.4 g.) indry dimethylformamide at 95° for 3 hours followed by "dry-column"chromatography on aluminum with ethanol as eluant gave4-(3-azidopropoxy)methylimidazole which was further purified by the samemethod using chloroform as eluant. The azide (2.95 g.) in ethanol (200ml.) was hydrogenated over platinum oxide catalyst to give4-(3-aminopropoxy)methylimidazole (2.42 g.).

Using the above prepared amine as the starting material in the procedureof Example 3(c) gives the title compound.

EXAMPLE 23N-[2-((2-Amino-4-imidazolyl)methylthio)ethyl]N'-cyano-N"-methylguanidine

Freshly prepared sodium amalgam (90 g.) is added over 75 minutes to astirred solution of serine ethyl ester dihydrochloride (3.0 g.) inwater/ethanol (2:), the temperature being maintained within the range offrom -12° to -10° and the pH at about 2.5 by the addition of 5Nhydrochloric acid. After a further 45 minutes the mixture is allowed towarm to 10° and the precipitated free mercury is removed, cyanamide isadded and the mixture warmed to 50° for 30 minutes, left at 0° for 18hours and evaporated to dryness. After washing with ether to remove anyunchanged cyanamide, the residue is extracted with hot ethanol andheated with hot ethanolic picric acid. Concentration and cooling of thesolution gives 2-amino-4-hydroxymethylimidazole picrate.

Reaction of 2-amino-4-hydroxymethylimidazole hydrochloride (which isobtained by treating the picrate salt with hydrochloric acid) withcysteamine hydrochloride by the procedure of Example 1 gives2-amino-4-[(2-aminoethyl)thiomethyl]imidazole.

By the procedure of Example 3(a),2-amino-4-[(2-aminoethyl)thiomethyl]imidazole is reacted withN-cyano-N',S-dimethylisothiourea to give the title compound. EXAMPLE 24

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-((4-methyl-5-                                         imidazolyl)methylthio)ethyl]guanidine                                                                   150 mg.                                             Sucrose                   75 mg.                                              Starch                    25 mg.                                              Talc                      5 mg.                                               Stearic acid              2 mg.                                               ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 25

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-[2-((4-Methyl-5-imidazolyl)methylthio)-                                     ethyl]-N'-nitroguanidine  200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 26

By the procedure of Example 1, using 3-hydroxymethylpyrazole as thestarting material, 2-(3-pyrazolylmethylthio)ethylguanidine sulphate isobtained.

Also, using 3-hydroxymethylpyrazole as the starting material, theprocedure of Example 2(i) and (ii) givesN-[2-(3-pyrazolymethylthio(ethyl]-N'-nitroguanidine, and the procedureof Example 2(iii) givesN-methyl-N'[2-(3-pyrazolylmethylthio)ethyl]-N"-nitroguanidine.

Using 3-[(2-aminoethyl)thiomethyl]pyrazole, prepared from3-hydroxymethylpyrazole by the procedure of Example 1, as the startingmaterial in the procedure of Example 3(c) givesN-cyano-N'-methyl-N"-[-(3-pyrazolylmethylthio)ethyl]guanidine.Hydrolysis by the method of Example 3(e) givesN-methyl-N'-[2-(3-pyrazolylmethylthio)ethyl]guanidine dihydrochloride.

Reacting 3-hydroxymethylpyrazole and 3-mercaptopropylamine by theprocedure of Example 1 and using the resulting3-[(3-aminopropyl)thiomethyl]pyrazole as the starting material in theprocedure of Example 3(a) givesN-cyano-N'-methyl-N"-[3-(3-pyrazolymethylthio)propyl]guanidine.

EXAMPLE 27

Reaction of 3-[(2-aminoethyl)thiomethyl]pyrazole withdimethyl-N-cyanoimidodithiocarbonate by the procedure of Example 3(c)(i)gives N-cyano-N'[2-(3-pyrazolylmethylthio)ethyl]-S-methylisothiourea.

Reaction of the above prepared isothiourea with anhydrous ethylamine bythe procedure of Example 4(a) givesN-cyano-N'-ethyl-N"-[2-(3-pyrazolylmethylthio)ethyl]guanidine.

By the same procedure, using propylamine,N-cyano-N'-propyl-N"-[2-(3-pyrazolylmethylthio)ethyl]guanidine isprepared.

Also, by the same procedure, using 2-(dimethylamino)ethylamine, theproduct isN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-pyrazolylmethylthio)ethyl]guanidine.

EXAMPLE 28

Using, in the procedure of Example 3, the followingaminoethylthiomethylpyrazoles, prepared by the procedure of Example 1from the corresponding hydroxymethylpyrazoles:

3-[(2-aminoethyl)thiomethyl]-5-methylpyrazole

4-[(2-aminoethyl)thiomethyl]-3,5-dimethylpyrazole

3-[(2-aminoethyl)thiomethyl]-5-hydroxypyrazole

3,4-di-[(2-aminoethyl)thiomethyl]pyrazole

the products are respectively:

N-cyano-N"-methyl-N"-[2-((5-methyl-3-pyrazolyl)-methylthio)ethyl]guanidine

N-cyano-N"-methyl-N"-[2-((3,5-dimethyl-4-pyrazolyl)methylthio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((5-hydroxy-3-pyrazolyl)methylthio)ethyl]guanidine

3,4-bis-[2-(N-cyano-N"-methylguanidino)ethylthiomethyl]pyrazole.

EXAMPLE 29 Using 4-hydroxy-3-hydroxymethylpyrazole (which is prepared byconverting 4-hydroxy-3-pyrazolecarboxylic acid to the correspondingethyl ester and reducing the ester with lithium aluminum hydride intetrahydrofuran) as the starting material in the procedure of Example 3givesN-cyano-N'-methyl-N"-[2-((4-hydroxy-3-pyrazolyl)methylthio)ethyl]guanidine.Hydrolysis of this compound by the procedure of Example 3(e) givesN-methyl-N'-[2-((4-hydroxy-3-pyrazolyl)methylthio)ethyl]guanidinehydrochloride. EXAMPLE 30N-Cyano-N'-methyl-N"-[2-(2-(3-pyrazolyl)ethyl)thioethyl]guanidine

By the procedure of Example 17 using 3-(2-chloroethyl)pyrazole (which isprepared by treating 3-(2-hydroxyethyl)pyrazole with thionyl chloride)as the starting material, the title compound is prepared.

EXAMPLE 31 N-Cyano-N'-methyl-N"-[3-(3-pyrazolylmethoxy)propyl]guanidine

By the procedure of Example 22, using 3-bromomethylpyrazole (prepared byreacting 3-hydroxymethylpyrazole with thionyl bromide) as the startingmaterial, the title compound is prepared.

EXAMPLE 32

By the procedure of Example 18, reacting3-[(2-aminoethyl)thiomethyl]pyrazole withdimethyl-N-cyanoimidodithiocarbonate and reacting the resultingN-cyano-N'-[2-(3-pyrazolylmethylthio)ethyl]-S-methylisothiourea withammoniacal ethanol givesN-cyano-N'-[2-(3-pyrazolylmethylthio)ethyl]guanidine.

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(3-pyrazolymethyl-                                    thio)ethyl]guanidine      200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atoms shown a five membered unsaturated heterocyclicring having two nitrogen atoms and three carbon atoms, said unsaturatedheterocyclic ring being imidazole or pyrazole, and Y is NH areexemplified by the following examples.

EXAMPLE 34 2-(4(5)-Imidazolylmethylamino)ethylguanidine sulphate

4(5) -Chloromethylimidazole (1.16 g., 0.01 m.) in 10 ml. of ethanol isadded slowly to excess ethylenediamine (6.0 g.) in 25 ml. of ethanol.The mixture is heated at 55° for 1 hour, then concentrated under reducedpressure and basified with sodium hydroxide. Evaporation under highvacuo and steam distillation followed by concentration to dryness,extraction with ethanol and acidification with ethanolic hydrogenchloride gives N-(4(5)-imidazolylmethyl)ethylenediamine.

The above prepared compound is heated under reflux withS-methylisothiouronium sulfate in water for 3 hours by the procedure ofExample 1 to give the title compound.

EXAMPLE 35

Reaction of N-(4(5)-imidazolylmethyl)ethylenediamine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-[2-(4(5)-imidazolylmethylamino)ethyl]-N'-nitroguanidine, and in theprocedure of Example 2(iii) givesN-methyl-N'-[2-(4-imidazolylmethylamino)ethyl]-N"-nitroguanidine.

EXAMPLE 36

Reacting 4(5)-chloromethylimidazole with ethylenediamine by theprocedure of Example 34, then reacting the resultingN-(4(5)-imidazolylmethyl)ethylenediamine withN-cyano-N',S-dimethylisothiourea in pyridine by the procedure of Example3 givesN-cyano-N'-[2-(4(5)-imidazolylmethylamino)ethyl]-N'-methylguanidine.Hydrolysis of this compound by the procedure of Example 3(e) givesN-methyl-N'-[2-(4-imidazolylmethylamino)ethyl]guanidinetrihydrochloride.

EXAMPLE 37

Ethylenediamine is reacted with 4(5)-chloromethylimidazole by theprocedure of Example 34 and the resultingN-(4(5)-imidazolylmethyl)ethylenediamine is reacted with ethylisothiocyanate by the procedure of Example 3(b) to give, afterconcentrating and chromatographing,N-ethyl-N'-[2-(4(5)-imidazolylmethylamino)ethyl]-thiourea. This thioureais reacted with lead cyanamide by the procedure of Example 3(b) to giveN-cyano-N'-ethyl-N"-[2-(4(5)-imidazolylmethylamino)ethyl]guanidine.

By the same procedure, using propyl isothiocyanate,N-cyano-N'-[2-(4(5)-imidazolylmethylamino)ethyl]N"-propylguanidine isprepared.

In the same manner, using 2-dimethylaminoethyl isothiocyanate, theproduct isN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(4(5)imidazolylmethylamino)ethyl]guanidine.

EXAMPLE 38N-Cyano-N'-[2-(2-(4(5)-imidazolyl)ethylamino)ethyl]-N"-methylguanidine

By the procedure of Example 34, reacting 4(5)-(2-chloroethyl)imidazolewith ethylenediamine gives N-[2-(4(5)-imidazolyl)ethyl]ethylenediamine.

Reacting the above prepared intermediate withN-cyano-N',S-dimethylisothiourea by the procedure of Example 3 gives thetitle compound.

EXAMPLE 39

Using, in the procedure of Example 36, in place of4(5)-chloromethylimidazole the following compounds (which may beprepared from the corresponding hydroxymethyl imidazoles by treatmentwith thionyl chloride):

4-chloromethyl-5-methylimidazole

4-chloromethyl-5-ethylimidazole

4-chloromethyl-5-isopropylimidazole

4-chloromethyl-5-benzylimidazole

4-chloromethyl-5-bromoimidazole

4-chloromethyl-2-methylimidazole

4-chloromethyl-1-methylimidazole

2-chloromethylimidazole

2-chloromethyl-1,5-dimethylimidazole

5-chloro-2-chloromethyl-1-methylimidazole

5-chloromethyl-4-trifluoromethylimidazole

2-amino-4-chloromethylimidazole

4,5-di(chloromethyl)imidazole the products are, respectively:

N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)-methylamino)ethyl]guanidin

N-cyano-N'-[2-((5-ethyl-4-imidazolyl)methylamino)-ethyl]-N"-methylguanidine

N-cyano-N'-[2-((5-isopropyl-4-imidazolyl)methylamino)-ethyl]N"-methylguanidine

N-cyano-N'-[2-((5-benzyl-4-imidazolyl)methylamino)-ethyl]-N"-methylguanidine

N-cyano-N'-[2-((5-bromo-4-imidazolyl)methylamino,ethyl]-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((2-methyl-4-imidazolyl)-methylamino)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((1-methyl-4-imidazolyl)-methylamino)ethyl]guanidine

N-cyano-N'-[2-(2-imidazolylmethylamino)ethyl]-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((1,5-dimethyl-2-imidazolyl)methylamino)ethyl]guanidine

N-cyano-N'-[2-((5-chloro-1-methyl-2-imidazolyl)-methylamino)ethyl]-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((4-trifluoromethyl-5-imidazolyl)methylamino)ethyl]guanidine

N-[2-((2-amino-4-imidazolyl)methylamino)ethyl]-N'-cyano-N"-methyl(guanidine

4,5-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]imidazole.

EXAMPLE 40

The reaction of 8.3 g. (0.1 m.) of 2-aminoimidazole and 13.3 g. (0.1 m.)of β-azidopropionyl chloride in pyridine gives2-(β-azidopropionyl)imidazole. Reduction of this compound with diboranein ethylene glycol/dimethyl ether yields2-(3-aminopropylamino)imidazole.

Using 2-(3-aminopropylamino)imidazole as the starting material in theprocedure of Example 3(b) givesN-cyano-N'-[3-(2-imidazolylamino)propyl]-N"-methylguanidine.

Reacting the above prepared compound with hydriodic acid gives thehydroiodide salt.

EXAMPLE 41

Using 2-(3-aminopropylamino)imidazole as the starting material in theprocedure of Example 18 givesN-cyano-N'-[3-(2-imidazolylamino)propyl]-S-methylisothiourea. Treatingthis compound with ammoniacal ethanol by the procedure of Example 18gives N-cyano-N'-[3-(2-imidazolylamino)propyl]guanidine.

EXAMPLE 42

    ______________________________________                                        ingredients                Amounts                                            ______________________________________                                        N-Cyano-N'-methyl-N"-[2-((5-methyl-4-                                         imidazolyl)methylamino)ethyl]guanidine                                                                  150 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are screened and filled into a hard gelatin capsule.

EXAMPLE 43

Reaction of 3-bromomethylpyrazole, prepared by treatment of3-hydroxymethylpyrazole with thionyl bromide, with ethylenediamine bythe procedure of Example 34 gives N-(3-pyrazolylmethyl)ethylenediamine.

The above prepared compound is heated under reflux withS-methylisothiouronium sulphate in water for 3 hours by the procedure ofExample 1 to give 2-(3-pyrazolylmethylamino)ethylguanidine sulphate.

EXAMPLE 44

Reaction of N-(3-pyrazolylmethyl)ethylenediamine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(3-pyrazolylmethylamino)-ethyl]guanidine, and in theprocedure of Example 2(iii) givesN-methyl-N'-[2-(3-pyrazolylmethylamino)ethyl]-N"-nitroguanidine.

EXAMPLE 45

Reacting 3-bromomethylpyrazole with ethylenediamine by the procedure ofExample 34 and reacting the resultingN-(3-pyrazolylmethyl)ethylenediamine withN-cyano-N',S-dimethylisothiourea by the procedue of Example 3(d) givesN-cyano-N'-methyl-N"-[2-(3-pyrazolylmethylamino)ethyl]guanidine.Hydrolysis of this compound by the procedure of Example 3(e) givesN-methyl-N'-[2-(3-pyrazolylmethylamino)ethyl]-guanidine trihyrochloride.

By the procedure of Example 3(b), reactingN-(3-pyrazolylmethyl)ethylenediamine with ethyl isothiocyanate, thenreacting the resultingN-ethyl-N'-[2-(3-pyrazolylmethylamino)ethyl]thiourea with lead cyanamidegives N-cyano-N'-ethyl-N"-[2-(3-pyrazolylmethylamino)ethyl]guanidine. Bythe same procedure, using propyl isothiocyanate the correspondingN'-propyl compound is prepared. Also, by the same procedure, using2-dimethylaminoethyl isothiocyanate, the product isN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-pyrazolylmethylamino)ethyl]-guanidine.

EXAMPLE 46

Using, in the procedure of Example 45, the following bromoalkylpyrazoles(which may be prepared by treating the hydroxyalkylpyrazoles withthionyl bromide):

5-methyl-3-bromomethylpyrazole

3,5-dimethyl-4-bromomethylpyrazole

5-hydroxy-3-bromomethylpyrazole

3,4-di(bromomethyl)pyrazole

3-(2-bromoethyl)pyrazole the products are, respectively:

N-cyano-N'-methyl-N"-[2-((5-methyl-3-pyrazolyl)-methylamino)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((3,5-dimethyl-4-pyrazolyl)methylamino)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((5-hydroxy-3-pyrazolyl)methylamino)ethyl]guanidine

3,4bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]pyrazole

N-cyano-N'-methyl-N"-[2-(2-(3-pyrazolyl)ethylamino)ethyl]guanidine.

EXAMPLE 47 2-[(4-Hydroxy-3-pyrazolyl)methylamino]ethylguanidine sulphate

4-Hydroxy-3-hydroxymethylpyrazole (which is prepared by converting4-hydroxy-3-pyrazolecarboxylic acid to the methyl ester and reducing theester with lithium aluminium hydride in tetrahydrofuran) is treated withthionyl bromide at room temperature to give3-bromomethyl-4-hydroxypyrazole.

Using 3-bromomethyl-4-hydroxypyrazole as the starting material in theprocedure of Example 43 gives the title compound.

EXAMPLE 48

Reaction of 3-aminopyrazole with β-azidopropionyl chloride by theprocedure of Example 40 gives 3-(3-aminopropylamino)pyrazole.

Using 3-(3-aminopropylamino)pyrazole as the intermediate in theprocedure of Example 36 givesN-cyano-N'-methyl-N"-[3-(3-pyrazolylamino)propyl]guanidine. Treatmentwith hydrobromic acid gives the hydrobromide salt.

Also, reacting 3-bromomethylpyrazole with 1,3-diaminopropane by theprocedure of Example 34 and using the resulting3-(3-aminopropylamino)methylpyrazole as the intermediate in theprocedure of Example 36 givesN-cyano-N'-methyl-N"-[3-(3-pyrazolylmethylamino)propyl]guanidine.

EXAMPLE 49

Using 3-(3-aminopropylamino)pyrazole as the starting material in theprocedure of Example 18 givesN-cyano-N'-[3-(3-pyrazolylamino)propyl]-S-methylisothiourea. Treatingthis compound with ammoniacal ethanol by the procedure of Example 18gives N-cyano-N'-[3-(3-pyrazolylamino)propyl]guanidine.

EXAMPLE 50

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(3-pyrazolylmethyl-                                   amino)ethyl]guanidine     200 mg.                                             Sucrose                   75 mg.                                              Starch                    25 mg.                                              Talc                      5 mg.                                               Stearic acid              2 mg.                                               ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atoms shown a six member unsaturated heterocyclic ringhaving two nitroge atoms and four carbon atoms, said unsaturatedheterocyclic ring being pyrimidine, pyrazine or pyridazine, and Y isoxygen or sulphur (sulphur is preferred) are exemplified by thefollowing examples.

EXAMPLE 51 2-(2-Pyrimidylmethylthio)ethylguanidine sulphate

A mixture of 5-bromo-2-hydroxymethylpyrimidine (5.6 g.) and magnesiumoxide (5.6 g.) in water/ethanol (2:1) was submitted to hydrogenolysisover 10% palladised charcoal for 0.5 hour. Filtration, concentration andether extraction from an aqueous solution of the residue afforded2-hydroxymethylpyrimidine (1.85 g.) as a mobile liquid. Reaction of thiscompound with thionyl chloride gives 2-chloromethylpyrimidine.

By the procedure of Example 1(i)(b), 2-chloromethylpyrimidine is reactedwith phthalimidoethanethiol and the product subjected to hydrazinolysis.The resulting 2-[(2-aminoethyl)thiomethyl]pyrimidine is reacted withS-methylisothiouronium sulphate to give the title compound.

EXAMPLE 52

Using 2-[(2-aminoethyl)thiomethyl]pyrimidine as the starting material inthe procedure of Example 2(ii) givesN-nitro-N'-[2-(2-pyrimidylmethylthio)ethyl]guanidine. Similarly, fromthe same starting material, according to the procedure of Example2(iii), there is producedN-methyl-N'-nitro-N"-[2-(2-pyrimidylmethylthio)ethyl]guanidine.

EXAMPLE 53

Reacting 2-chloromethylpyrimidine with phthalimidoethanethiol by theprocedure of Example 1(i)(b) and then reacting the resulting2-[(2-aminoethyl)thiomethyl]-pyrimidine withdimethyl-N-cyanoimidodithiocarbonate and methylamine by the procedure ofExample 3(d) givesN-cyano-N'-methyl-N"-[2-(2-pyrimidylmethylthio)ethyl]-guanidine.

Also, reacting 2-hydroxymethylpyrimidine with 3-mercaptopropylamine bythe procedure of Example 1 and then reacting the resulting2-[(3-aminopropyl)thiomethyl]-pyrimidine withdimethyl-N-cyanoimidodithiocarbonate and methylamine by the procedure ofExample 3(d) givesN-cyano-N'-methyl-N"-[3-(2-pyrimidylmethylthio)propyl]guanidine.

EXAMPLE 54

Using the following chloromethylpyrimidine compounds (prepared wherenecessary from the corresponding hydroxyethyl compounds and thionylchloride) in the procedure of Example 53:

4-chloromethyl-6-methylpyrimidine

2-chloromethyl-5-methylpyrimidine

4-hydroxy-2-chloromethylpyrimidine

5-bromo-2-chloromethylpyrimidine

2-chloro-4-chloromethylpyrimidine

2-amino-4-chloromethylpyrimidine

5-chloromethyl-2,4-dimethylpyrimidine

4-chloro-5-chloromethyl-2-methylpyrimidine products are, respectively:

N-cyano-N'-methyl-N"-[2-((6-methyl-4-pyrimidyl)methylthio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((5-methyl-2-pyrimidyl)methylthio)ethyl]guanidine

N-cyano-N'-[2-((4-hydroxy-2-pyrimidyl)methylthio)-ethyl]-N'-methylguanidine

N-[2-((5-bromo-2-pyrimidyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

N-[2-((2-chloro-4-pyrimidyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

N-[2-((2-amino-4-pyrimidyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-[2-((2,4-dimethyl-5-pyrimidyl)methylthio)ethyl]-N"-methylguanidine

N-[2-((4-chloro-2-methyl-5-pyrimidyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.

EXAMPLE 55

Reaction of 2-[(2-aminoethyl)thiomethyl]pyrimidine withdimethyl-N-cyanoimidodithiocarbonate by the procedure of Example 3(c)(i)gives N-cyano-N'-[2-(2-pyrimidylmethylthio)ethyl]-S-methylisothiourea.

Reaction of the above prepared isothiourea with anhydrous ethylamine bythe procedure of Example 4 givesN-cyano-N'-ethyl-N"-[2-(2-pyrimidylmethylthio)ethyl]guanidine.

By the same procedure using propylamine the corresponding N'-propylguanidine is prepared.

Also, by the same procedure using 2-(dimethylamino)ethylamine, theproduct isN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(2-pyrimidylmethylthio)ethyl]guanidine.

EXAMPLE 564,6-bis-[2-(N-Cyano-N'-methylguanidino)ethylthiomethyl]pyrimidine

4,6-Pyrimidinecarboxylic acid is converted to the dimethyl ester and theester is reduced with lithium aluminum hydride in tetrahydrofuran togive 4,6-di(hydroxymethyl)pyrimidine, which on treatment with hionylchloride gives 4,6-di(chloromethyl)pyrimidine.

Using 4,6-di(chloromethyl)pyrimidine in the procedure of Example 53gives the title compound.

EXAMPLE 57N-Cyano-N'-methyl-N"-[2-(2-(2-(2-pyrimidyl)ethyl)thioethyl]-guanidine

By the procedure of Example 17 using 2-(2-chloroethyl)pyrimidine,prepared by treating 2-(2-hydroxyethyl)pyrimidine with thionyl chloride,as the starting material, 2-[2-(2-aminoethyl)thioethyl]pyrimidine isprepared, which when treated with N-cyano-N', S-dimethylisothiourea bythe procedue of Example 3(a) gives the title compound.

EXAMPLE 58 N-Cyano-N'-methyl-N"-[3-(2-pyrimidylmethoxy)propyl]guanidine

By the procedure of Example 22 using 2-chloromethylpyrimidine, preparedby treating 2-hydroxymethylpyrimidine with thionyl chloride, the titlecompound is prepared.

EXAMPLE 59

A mixture of 2-mercaptopyrimidine (5.6 g.) and 3-bromopropylphthalimide(13.4 g.) in ethanol (100 ml.) containing sodium (1.15 g.) was heatedunder reflux for 20 hours to give 2-(3-phthalimidopropylthio)pyrimidine,m.p. 81.5°-82.5° (from ethanol-water). Reaction of the phthalimidocompound (3.7 g.) and hydrazine (1.86 g.) followed by reaction of theproduct directly with N-cyano-N',S-dimethylisothiourea by the procedureof Example 3(a) givesN-cyano-N'-methyl-N"-[3-(2-pyrimidylthio)propyl]guanidine.

By the same procedure, using 4-mercapto-2-trifluoromethylpyrimidine(prepared by reacting 4-hydroxy-2-trifluoromethylpyrimidine withphosphorus pentasulfide),N-cyano-N'-methyl-N"-[3-(2-trifluoromethyl-4-pyrimidylthio)propyl]guanidineis prepared.

EXAMPLE 60

Reaction of 2-(3-aminopropylthio)pyrimidine withdimethyl-N-cyanoimidodithiocarbonate and then with ammonia by theprocedure of Example 18 givesN-cyano-N'-[3-(2-pyrimidylthio)propyl]guanidine.

EXAMPLE 61

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N" -[2-(2-pyrimidyl-                                        methylthio)ethyl]guanidine                                                                              150 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 62 2-(2-Pyrazinylmethylthio)ethylguanidine sulphate

2-Chloromethylpyrazine (6.4 g.) was added over 20 minutes to a solutionfreshly pepared from sodium (0.23 g.) in ethanol (50 ml.) to whichcysteamine hydrochloride (5.7 g.) had been added gradually at 0° andstirred at this temperature for 2 hours. The suspension finally obtainedwas stirred at room temperature overnight, acidified with hydrochloricacid (pH 5) and concentrated under reduced pressure. The dry residue wasextracted with ethanol and the extracts filtered and concentrated togive the crude product. Extraction with isopropyl alcohol, with theremoval of some polymeric material and the addition of ether gave acream coloured solid (3.5 g.), which was recrystallised fromethanol-ether to furnish 2-[(2-aminoethyl)thiomethyl]pyrazinehydrochloride m.p. 144°-146°.

The amine hydrochloride (1.6 g.) was converted into the free base andreacted with S-methylisothiouronium sulphate by the procedue of Example1 to give the title compound.

EXAMPLE 63

Reaction of 2-[(2-aminoethyl)thiomethyl]pyrazine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(2-pyrazinylmethylthio)-ethyl]guanidine. Similarly by theprocedure of Example 2(iii), there is preparedN-methyl-N'-nitro-[2-(2-pyrazinylmethylthio)ethyl]guanidine.

EXAMPLE 64N-Cyano-N'-methyl-N"-[2-(2-pyrazinylmethylthio)ethyl]guanidine

Reaction of 2-[(2-aminoethyl)thiomethyl]pyrazine withdimethyl-N-cyanoimidodithiocarbonate by the procedure of Example 3(c)(i)gives N-cyano-N'-[2-(2-pyrazinylmethylthio)ethyl]-S-methylisohiourea.

Reaction of this isothiourea with methylamine by the procedure ofExample 3(c)(ii) gives the title compound.

EXAMPLE 65

Anhydrous ethylamine is reacted withN-cyano-N'-[2-(2-pyrazinylmethylthio)ethyl]-S-methylisothiourea by theprocedure of Example 4 to giveN-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylthio)ethyl]guanidine.

By the same procedure, using propylamine the corresponding N'-propylguanidine is prepared. Using 2-(dimethylamino)ethylamine thecorresponding N'-(2-dimethylaminoethyl) guanidine is prepared.

EXAMPLE 66

By the procedure of Example 62, the following chloromethylpyrazines:

2-chloromethyl-5-methylpyrazine

2-chloromethyl-3-methylpyrazine

3-chloro-2-chloromethylpyrazine

3-amino-2-chloromethylpyrazine

2,3-di(chloromethyl)pyrazine are converted to the corresponding2-[(2-aminoethyl)thio methyl]pyrazines and these intermediates are usedas starting materials in the procedure of Example 3 to give thefollowing producs:

N-cyano-N'-methyl-N"-[2-((5-methyl-2-pyrazinyl)methylhio)ethyl]guanidine.

N-cyano-N'-methyl-N"-[2-((3-methyl-2-pyrazinyl)methylhio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((3-chloro-2-pyrazinyl)methylthio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((3-amino-2-pyrazinyl)-methylthio)ethyl]guanidine

2,3-bis-[2(N-cyano-N'-methylguanidino)ethylthiomethyl]pyrazine.

EXAMPLE 67

3-Hydroxypyrazine-2-carboxylic acid is converted to the methyl ester andthe ester is reduced with lithium aluminium hydride in tetrahydrofuranto give 3-hyroxy-2-hydroxymethylpyrazine. Treatment of3-hydroxy-2-hydroxymethylpyrazine at room temperature with thionylchloride gives 3-hydroxy-2-chloromethylpyrazine and reacting thisintermediate with cysteamine by the procedure of Example 62 gives2-[(2-aminoethyl)thiomethyl]-3-hydroxypyrazine.

Using 2-[(2-aminoethyl)thiomethyl]-3-hydroxypyrazine as the startingmaterial in the procedure of Example 3(c) givesN-cyano-N'-[2-((3-hydroxy-2-pyrazinyl)methylthio)ethyl]-N"-methylguanidine

By the same procedure, using 3,6-dimethylpyrazine-2-carboxylic acid asthe starting material, the product isN-cyano-N'-[2-((3,6-dimethyl-2-pyrazinyl)methylthio)ethyl]-N"-methylguanidine.

Reduction of 3-chloro-5-methyl-2-pyrazinecarboxylic acid with diboranegives 3-chloro-2-hydroxymethyl-5-methylpyrazine which, using the aboveprocedure, yieldsN-[2-((3-chloro-5-methyl-2-pyrazinyl)methylthio)ethyl]N'-cyano-N"-methylguanidine.

By the above procedure, using 3-hydroxy-2-chloromethylpyrazine and,instead of cysteamine, using 3-mercaptopropylamine, the product obtainedisN-cyano-N'-[3-((3-hydroxy-2-pyrazinyl)methylthio)propyl]-N"-methylguanidine.

EXAMPLE 68N-Cyano-N"-methyl-N"-[2-(2-(2-pyrazinyl)ethyl)thioethyl]guanidine

Using 2-(2-chloroethyl)pyrazine, prepared by reacting2-(2-hydroxyethyl)pyrazine with thionyl chloride, as the startingmaterial in the procedure of Example 57 gives the title compound.

EXAMPLE 69 N-Cyano-N'-methyl-N"-[3-(2-pyrazinylthio)propyl]guanidine

Using 2-mercaptopyrazine as the starting material in the procedure ofExample 59 gives the title compound.

EXAMPLE 70 N-Cyano-N'-methyl-N"-[2-(2-pyrazinylmethoxy)ethyl]guanidine

2-Chloromethylpyrazine is reacted with the sodium salt of ethyleneglycol to give 2-(2-hydroxyethoxymethyl)pyrazine which is treated withthionyl chloride to give 2(2-chloroethoxymethyl)pyrazine. Using thisintermediate in place of 4-(3-chloropropoxy)methylimidazole in theprocedure of Example 22 gives the title compound.

EXAMPLE 71

Using 2-[(2-aminoethyl)thiomethyl]pyrazine as the starting material inthe procedure of Example 18 givesN-cyano-N'-[2-(2-pyrazinylmethylthio)ethyl]guanidine.

EXAMPLE 72

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(2-pyrazinyl-                                         methylthio)ethyl]guanidine                                                                              200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 73 2-(3-Pyridazinylmethylthio)ethylguanidine sulphate

By the procedure of Example 1, using 3-hydroxymethylpyridazine, theintermediate 3-[(2-aminoethyl)thiomethyl]pyridazine dipicrate, m.p.145°-148° is prepared. Converting this picrate to the dihydrobromide,then to the free base by the procedure of Example 1 and reacting the3-[(2-aminoethyl)thiomethyl]pyridazine with S-methylsiothiouroniumsulphate by the procedure of Example 1 gives the title compound.

EXAMPLE 74

Reaction of 3-[(2-aminoethyl)thiomethyl]pyridazine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(3-pyridazinylmethylthio)ethyl)guanidine. Similarly, bythe procedure of Example 2(iii), there is obtainedN-methyl-N'-nitro-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.

EXAMPLE 75

Reacting 3-hydroxymethylpyridazine with cysteamine by the procedure ofExample 1 and then reacting the resulting3-[(2-aminoethyl)thiomethyl]pyridazine withdimethyl-N-cyanoimidodithiocarbonate by the procedure of Example 3(c)(i)gives N-cyano-N'-[2-(3-pyridazinylmethylthio)ethyl]-S-methylisothiourea.

Reacting this isothiourea with methylamine by the procedure of Example3(c)(ii) givesN-cyano-N'-methyl-N"-[2(3-pyridazinylmethylthio)ethyl]guanidine.

Treating this product with hydrobromic acid gives the hydrobromide salt.

Hydrolysis ofN-cyano-N'-methyl-N"-[2-(3-pyridazinylmetylthio)ethyl]guanidine by theprocedure of Example 3(e) givesN-methyl-N'-[2-(3-pyridazinylmethylthio)ethyl]guanidine.

EXAMPLE 76

Anhydrous ethylamine is reacted withN-cyano-N'-[2-(3-pyridazinylmethylthio)ethyl]-S-methylisothiourea by theprocedure of Example 4 to giveN-cyano-N'-ethyl-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.

Using 2-(dimethylamino)ethylamine, the product isN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.

EXAMPLE 77

Using in the procedure of Example 75 the followinghydroxymethylpyridazines:

4-hydroxymethyl-6-methylpyridazine

4-hydroxymethyl-3,6-dimethylpyridazine

3-chloro-4-hydroxymethyl-6-methylpyridazine

4,5-di(hydroxymethl)pyridazine the products are respectively:

N-cyano-N'-methyl-N"-[2-((6-methyl-4-pyridazinyl)methylthio)guanidine

N-cyano-N'-[2-((3,6-dimethyl-4-pyridazinyl)methylthio)ethyl]-N"-methylguanidine

N-[2-((3-chloro-6-methyl-4-pyridazinyl)methylthio)-ethyl]-N'-cyano-N"-methylguanidine

4,5-bis-[2-(N-cyano-N'-methylguanidino)ethylthiomethyl)pyridazine.

Using in the procedure of Example 75, 3-mercaptopropylamine in place ofcysteamine, the product isN-cyano-N'-methyl-N"-[3-(3-pyridazinylmethylthio)propyl]-guanidine.

EXAMPLE 78

6-Amino-3-pyridazinecarboxylic acid is converted to the ethyl ester andthe ester is reduced with lithium aluminium hydride in tetrahydrofuranto give 6-amino-3-hydroxymethylpyridazine.

Using 6-amino-3-hydroxymethylpyridazine as the starting material in theprocedure of Example 75 givesN-[2-((6-amino-3-pyridazinyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

By the same procedure, using 6-hydroxy-3-pyridazinecarboxylic acid asthe starting material,N-cyano-N'-[2-((6-hydroxy-3-pyridazinyl)methylthio)ethyl]-N"-methylguanidineis prepared.

Reduction of 6-chloro-3-pyridazinecarboxylic acid with diborane gives6-chloro-3-hydroxymethylpyridazine which, in the procedure of Example75, givesN-[2-((6-chloro-3-pyridazinyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.

EXAMPLE 79 N-Cyano-N'-methyl-N"-[2-(2l-(3-pyridazinyl)ethyl)-thioethyl]guanidine

3-Cyanomethylpyridazine is treated with aqueous sodium hydroxide to give3-pyridazineacetic acid.

3-Pyridazineacetic acid is esterified with anhydrous ethanolic hydrogenchloride and the resulting ethyl ester is reduced with lithium aluminiumhydride in tetrahydrofuran to give 3-(2-hydroxyethyl)pyridazine.Treating this hydroxyethyl compound with thionyl chloride gives3-(2-chloroethyl)pyridazine.

Using 3-(2-chloroethyl)pyridazine as the starting material in theprocedure of Example 17 gives the title compound.

EXAMPLE 80 N-Cyano-N'-methyl-N"-[3-(3-pyridazinylthio)-propyl]-guanidine

Using 3-mercaptopyridazine as the starting material in the procedure ofExample 20 gives the title compound.

EXAMPLE 81N-Cyano-N'-methyl-N"-[3-(3-pyridazinylmethoxy)-propyl]-guanidine

Using 3-chloromethylpyridazine, prepared by reacting3-hyroxymethylpyridazine with thionyl chloride, as the starting materialin the procedure of Example 22 gives the title compound.

EXAMPLE 82

Using 3-[(2-aminoethyl)thiomethyl]pyridazine as the starting material inthe procedure of Example 18 givesN-cyano-N'-[2-(3-pyridazinylmethylthio)ethyl]-guanidine.

EXAMPLE 83

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(3-pyridazinyl-                                       methylthio)ethyl]guanidine                                                                              200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a six membered unsaturated heterocyclic ringhaving two nitrogen atoms and four carbon atoms, said unsaturatedheterocyclic ring being pyrimidine, pyrazine or pyridazine, and Y is NHare exemplifed by the following examples.

EXAMPLE 84 2-(2-Pyrimidylmethylamino)ethylguanidine sulphate

By the procedure of Example 34, ethylenediamine is reacted with2-chloromethylpyrimidine, prepared by treating 2-hydroxymethylpyrimidinewith thionyl chloride to give N-(2-pyrimidylmethyl)ethylenediamine.

The above prepared compound is heated under reflux withS-methylisothiouronium sulphate in water for 3 hours by the procedure ofExample 1 to give 2-(2-pyrimidylmethylamino)ethylguanidine sulphate.

EXAMPLE 85

Reaction of N-(2-pyrimidylmethyl)ethylenediamine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(2-pyrimidylmethylamino)-ethyl]guanidine. Similarly, fromthe same starting material, according to the procedure of Example2(iii), there is producedN-methyl-N'-nitro-N"-[2-(2-pyrimidylmethylamino)ethyl]guanidine.

EXAMPLE 86N-Cyano-N'-methyl-N"-[2-(2-pyrimidylmethylamino)ethyl]guanidine

Reaction of 2-chloromethylpyrimidine with ethylenediamine by theprocedure of Example 34 and reaction of the resultingN-(2-pyrimidylmethyl)ethylenediamine with methyl isothiocyanate by theprocedure of Example 3(b) gives, after concentrating andchromatographing,N-methyl-N'-[2-(2-pyrimidylmethylamino)ethyl]-thiourea. This thiorea isreacted with lead cyanamide by the procedure of Example 3(b) to give thetitle compound.

EXAMPLE 87

Using ethyl isothiocyanate in place of methyl isothiocyanate in theprocedure of Example 86 givesN-cyano-N'-ethyl-N"-[2-(2-pyrimidylmethylamino)ethyl]guandine.

By the same procedure, using propyl isothiocyanate, the product isN-cyano-N'-propyl-N"-[2-(2-pyrimidylmethylamino)ethyl]guanidine.

Also, using 2-dimethylaminoethyl isothiocyanate, the product isN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(2-pyrimidylmethylamino)ethyl]guanidine.

EXAMPLE 88

Using, in the procedure of Example 86, the followinghaloalkylpyrimidines (which may be prepared by treating thecorresponding hydroxyalkylpyrimidines with a thionyl halide):

5-bromomethylpyrimidine

2-chloromethyl-5-methylpyrimidine

5-bromo-2-bromomethylpyrimidine

2-bromomethyl-4-hydroxypyrimidine

4-amino-5-bromomethylpyrimidine

5-bromomethyl-2,4-dimethylpyrimidine

4-chloro-5-chloromethyl-2-methylpyrimidine

4-(2-bromoethyl)pyrimidine

4,6-di(bromomethyl)pyrimidine the products are, respectively:

N-cyano-N'-methyl-N"-[2-(5-pyrimidylmethylamino)-ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((5-methyl-2-pyrimidyl)-methylamino)ethyl]guanidine

N-[2-((5-bromo-2-pyrimidyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-[2-((4-hydroxy-2-pyrimidyl)methylamino)-ethyl]-N"-methylguanidin

N-[2-((4-amino-5-pyrimidyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((2,4-dimethyl-5-pyrimidyl)-methylamino)ethyl]guanidine

N-[2-((4-chloro-2-methyl-5-pyrimidyl)methylamino)-ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-(2-(2-pyrimidyl)ethylamino)-ethyl]guanidine

4,6-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]pyrimidine.

Using, in the procedure of Example 86, 1,3-diaminopropane in place ofethylenediamine, the product isN-cyano-N'-methyl-N"-[3-(2-pyrimidylmethylamino)propyl]-guanidine.

EXAMPLE 89

Reaction of 2-bromopyrimidine with 1,3-diaminopropane in ethanolcontaining sodium ethoxide gives 2-(3-aminopropylamino)pyrimidine.

Using 2-(3-aminopropylamino)pyrimidine as the starting material in theprocedure of Example 3(a) givesN-cyano-N'-methyl-N"-[3-(2-pyrimidylamino)propyl]guanidine.

By the same procedure, using 4-chloro-2-trifluoromethylpyrimidine(prepared by treating 4-hydroxy-2-trifluoromethylpyrimidine withphosphorus oxychloride and dimethylaniline), the product isN-cyano-N'-methyl-N"-[3-(2-trifluoromethyl-4-pyrimidylamino)propyl]guanidine.

EXAMPLE 90

Using 2-(3-aminopropylamino)pyrimidine as the starting material in theprocedure of Example 18 givesN-cyano-N'-[3-(2pyrimidylamino)propyl]guanidine.

EXAMPLE 91

    ______________________________________                                        Ingredient                Amount                                              ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(2-pyrimidyl-                                         methylamino)ethyl]guanidine                                                                             200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 92

Ethylenediamine is reacted with 2-chloromethylpyrazine by the procedureof Example 34 to give N-(2-pyrazinylmethyl)ethylenediamine. Heating thiscompound with S-methylisothiourea in water under reflux for 3 hours bythe procedure of Example 1 gives2-(2-pyrazinylmethylamino)ethylguanidine.

EXAMPLE 93

Reacting N-(2-pyrazinylmethyl)ethylenediamine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(2-pyrazinylmethylamino)ethyl]guanidine. Similarly, fromthe same starting material, according to the procedure of Example2(iii), there is producedN-methyl-N'-nitro-N"-[2-(2-pyrazinylmethylamino)ethyl]guanidine.

EXAMPLE 94N-Cyano-N'-methyl-N"-[2-(2-pyrazinylmethylamino)ethyl]-guanidine

Reacting 2-chloromethylpyrazine with ethylenediamine by the procedure ofExample 34 and reacting the resultingN-(2-pyrazinylmethyl)ethylenediamine withN-cyano-N',S-dimethylisothiourea by the procedure of Example 3 gives thetitle compound.

EXAMPLE 95

Reacting N-(2-pyrazinylmethyl)ethylenediamine with ethyl isothiocyanateby the procedure of Example 3 and chromatographing givesN-ethyl-N'-[2-(2-pyrazinylmethylamino)ethyl]thiourea. Reacting thisthiourea with lead cyanamide by the procedure of Example 3 givesN-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylamino)ethyl]-guanidine.

By the same procedure, using 2-dimethylaminoethyl isothiocyanate, theproduct isN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(2-pyrazinylmethylamino)ethyl]-guanidine.

EXAMPLE 96 2-[(5-Methyl-2-pyrazinyl)methylamino]ethylguanidine

Using 2-chloromethyl-5-methylpyrazine as the starting material in theprocedure of Example 34 gives the title compound.

EXAMPLE 97

Using in the procedure of Example 94, the following haloalkylpyrazines(which may be prepared by treating the correspondinghydroxyalkylpyrazines with a thionyl halide):

2-chloromethyl-3-methylpyrazine

3-chloro-2-chloromethylpyrazine

3-amino-2-chloromethylpyrazine

2,3-di(chloromethyl)pyrazine

2-chloromethyl-3-hydroxypyrazine

2-chloromethyl-3,6-dimethylpyrazine

3-chloro-2-chloromethyl-5-methylpyrazine

2-(2-chloroethyl)pyrazine the products are, respectively:

N-cyano-N'-methyl-N"-[2-((3-methyl-2-pyrazinyl)-methylamino)ethyl]guanidine

N-[2-((3-chloro-2-pyrazinyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-[2-((3-amino-2-pyrazinyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

2,3-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]pyrazine

N-cyano-N'-[2-((3-hydroxy-2-pyrazinyl)methylamino)ethyl-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((3,6-dimethyl-2-pyrazinyl)methylamino)ethyl]guanidine

N-[2-((3-chloro-5-methyl-2-pyrazinyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-(2-(2-pyrazinyl)ethylamino)ethyl]guanidine.

Using in the procedure of Example 94, 1,3-diaminopropane in place ofethylenediamine gives, as the product,N-cyano-N'-methyl-N"-[3-(2-pyrazinylmethylamino)propyl]guanidine.

EXAMPLE 98 N-Cyano-N'-methyl-N"-[3-(2-pyrazinylamino)propyl]guanidine

Reacting 2-chloropyrazine with 1,3-diaminopropane in ethanol containingsodium ethoxide by the procedure of Example 89 gives2-(3-aminopropylamino)-pyrazine.

Using 2-(3-aminopropylamino)pyrazine as the starting material in theprocedure of Example 3(a) gives the title compound

EXAMPLE 99

Using 2-(3-aminopropylamino)pyrazine as the starting material in theprocedure of Example 18 givesN-cyano-N'-[3-(2-pyrazinylamino)propyl]guanidine.

EXAMPLE 100

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(2-pyrazinyl-                                         methylamino)ethyl]guanidine                                                                             200 mg.                                             Sucrose                   75 mg.                                              Starch                    25 mg.                                              Talc                      5 mg.                                               Stearic acid              2 mg.                                               ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 101 2-(3-Pyridazinylmethylamino)ethylguanidine sulphate

Reacting ethylenediamine with 3-chloromethylpyridazine by the procedureof Example 34 gives N-(3-pyridazinylmethyl)ethylenediamine. Thisintermediate is reacted with S-methylisothiouronium sulphate by theprocedure of Example 1 to give the title compound.

EXAMPLE 102

Reacting N-(3-pyridazinylmethyl)ethylenediamine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(3-pyridazinylmethylamino)ethyl]guanidine. Treatment withhydrobromic acid gives the hydrobromide salt.

Similarly, by the procedure of Example 2(iii), there is producedN-methyl-N'-nitro-N"-[2-(3-pyridazinylmethylamino)ethyl]guanidine.

EXAMPLE 103

Reacting 3-chloromethylpyridazine with ethylenediamine by the procedureof Example 34 and reacting the resultingN-(3-pyridazinylmethyl)ethylenediamine with methyl isothiocyanate by theprocedure of Example 3(b), then chromatographing givesN-methyl-N'-[2-(3pyridazinylmethylamino)ethyl]thiourea. Thisintermediate is reacted with lead cyanamide by the procedure of Example3(b) to giveN-cyano-N'-methyl-N"-[2-(3-pyridazinylmethylamino)-ethyl]guanidine.Hydrolysis of this compound by the procedure of Example 3(e) givesN-methyl-N'-[2-(3-pyridazinylmethylamino)ethyl]guanidinedihydrochloride.

EXAMPLE 104

Using ethyl isothiocyanate in place of methyl isothiocyanate in theprocedure of Example 103 givesN-cyano-N'-ethyl-N"-[2-(3pyridazinylmethylamino)ethyl]guanidine.

Using 2-dimethylaminoethyl isothiocyanate in the above procedure givesN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-pyridazinylmethylamino)ethyl]guanidine.

EXAMPLE 105

Using, in the procedure of Example 103, the followingchloroalkylpyridazines (which may be prepared by treating thehydroxyalkylpyridazines with thionyl chloride):

4-chloromethyl-6-methylpyridazine

4-chloromethyl-3,6-dimethylpyridazine

3-chloro-4-chloromethyl-6-methylpyridazine

4,6-di(chloromethyl)pyridazine

6-amino-3-chloromethylpyridazine

6-chloro-3-chloromethylpyridazine

3-chloromethyl-6-hydroxypyridazine

3-(2-chloroethyl)pyridazine the products are, respectively:

N-cyano-N'-methyl-N"-[2-((6-methyl-4-pyridazinyl)-methylamino)ethyl]guanidine.

N-cyano-N'-methyl-N"-[2-((3,6-dimethyl-4-pyridazinyl)-methylamino)ethyl]guanidine

N-[2-((3-chloro-6-methyl-4-pyridazinyl)methylamino)-ethyl]-N'-cyano-N"-methylguanidine

4,6-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]pyridazine

N-[2-((6-amino-3-pyridazinyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-[2-((6-chloro-3-pyridazinyl)methylamino)ethyl]-N'-cyano-N"-methylguanidin

N-cyano-N'-[2-((6-hydroxy-3-pyridazinyl)methylamino)-ethyl]-N"-methylguanidine

N-cyano-N'-methyl-[2-(2-(3-pyridazinyl)ethyl)aminoethyl]guanidine.

Using 1,3-diaminopropane in place of ethylenediamine in the procedure ofExample 103 givesN-cyano-N'-methyl-N"-[3-(3-pyridazinylmethylamino)propyl]-guanidine.

EXAMPLE 106

Reacting 3-chloropyridazine with 1,3-diaminopropane in ethanolcontaining sodium ethoxide according to the procedure of Example 89gives 3-(3-aminopropylamino)-pyridazine. Using this intermediate as thestarting material in the procedure of Example 18 givesN-cyano-N'-[3-(3-pyridazinylamino)propyl]guanidine.

EXAMPLE 107

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(3-pyridazinyl-                                       methylamino)ethyl]guanidine                                                                             150 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I where A is such that there is formed togetherwith the carbon atom shown a five membered unsaturated heterocyclic ringhaving one nitrogen atom, one sulphur or oxygen atom and three carbonatoms, said unsaturated heterocyclic ring being thiazole, isothiazole,oxazole or isoxazole, and Y is oxygen or sulphur (sulphur is preferred)are exemplified by the following examples.

EXAMPLE 108

By the procedure of Example 1, using as the starting materials2-hydroxymethylthiazole and 4-hydroxymethylthiazole, were produced thefollowing intermediate amine salts:

2-[(2-aminoethyl)thiomethyl]thiazole dihydrobromide, m.p. 144°-147.5° C.

4-[(2-aminoethyl)thiomethyl]thiazole dihydrobromide, m.p. 197°-203° C.

These amine salts were converted to the free bases and reacted withS-methylisothiouronium sulphate by the procedure of Example 1 to givethe following products:

2-(2-thiazolylmethylthio)ethylguanidine sulphate

2-(4-thiazolylmethylthio)ethylguanidine sulphate.

EXAMPLE 109

Reaction of 2-[(2-aminoethyl)thiomethyl]thiazole withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(2-thiazolylmethylthio)-ethyl]guanidine.

Also, reaction of the same starting material withN,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii)gives N-methyl-N'-nitro-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine.

EXAMPLE 110N-Cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine

a. Reaction of [(2-aminoethyl)thiomethyl]thiazole (from thedihydrobromide 20.2 g.) with N-cyano-N',S-dimethylisothiourea (7.75 g.)by a procedure similar to that described in Example 3(a) affordedN-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine, m.p.120°-122.5°, following chromatography on silica gel with acetonitrile aseluant, and recrystallisation from isopropyl alcohol. (Found: C, 42.3;H, 5.1; N, 27.2; S, 25.3. C₉ H₁₃ N₅ S₂ requires: C, 42.3; H, 5.1; N,27.4; S, 25.1).

b. The sequential reaction of dimethyl-N-cyanoimidodithiocarbonate (5.5g.) with 2-[(2-aminoethyl)thiomethyl]-thiazole (from the dihydrobromide)(12.0 g.) and excess methylamine by the procedure described in Example3(d) affordedN-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)-ethyl]guanidine (8.46g.), m.p. 121°-123° (from isopropyl alcohol).

Hydrolysis ofN-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine by theprocedure of Example 3(e) givesN-methyl-N'-[2-(2-thiazolylmethylthio)ethyl]guanidine dihydrochloride.

EXAMPLE 111

Reaction ofN-cyano-N'-[2-(2-thiazolylmethylthio)ethyl]-S-methylisothiourea,prepared from 2-[(2-aminoethyl)thiomethyl]thiazole by the procedure ofExample 3(c)(i), with ethylamine by the procedure of Example 4 givesN-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine.

Similarly, using propylamine and 2-(dimethylamino)ethylamine, theproducts are respectively:

N-cyano-N'-propyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine

N-cyano-N'-(2-dimethylaminoethyl)-N'-[2-(2-thiazolylmethylthio)ethyl]guanidine.

EXAMPLE 112 N-Cyano-N'-methyl-N"-[3-(2thiazolylthio)propyl]-guanidine

By the procedure of Example 20, using 2-mercaptothiazole as the startingmaterial, the intermediate amine salt, 2-(3-aminopropylthio)thiazoledihydrobromide, m.p. 175°-178° C., was prepared.

The above prepared amine salt is converted to the free base and reactedwith N-cyano-N,S-dimethylisothiourea by the procedure of Example 3(a) togive the title compound.

EXAMPLE 113N-Cyano-N'-methyl-N"-[2-(5-thiazolylmethylthio)ethyl]guanidine

i. The reaction of 5-hydroxymethylthiazole (2.01 g.) with cysteaminehydrochloride (1.99 g.) in aqueous hydrobromic acid by the methoddescribed in Example 1(i)(a) gave 5-((2-aminoethyl)thiomethyl)thiazoledihydrobromide (4.85 g.) m.p. 191°-194° (from methanol).

ii. The reaction of 5-((2-aminoethyl)thiomethyl)thiazole (2.24 g.) withmethyl isothiocyanate (0.94 g.) in ethanol (10 ml.) gave a thioureawhich was purified by chromatography on a column of silica gel withethyl acetate as eluant. Recrystallisation from isopropyl acetate-methylethyl ketone-ether gaveN-methyl-N'-[2-(5-thiazolylmethylthio)ethyl]thiourea (2.1 g.) m.p.86°-88°.

iii. The reaction ofN-methyl-N'-[2-(5-thiazolylmethylthio)ethyl]thiourea with lead cyanamideby the procedure of Example 3(b) gives the title compound.

EXAMPLE 114N-Cyano-N'-methyl-N"-[2-((2-amino-4-thiazolyl)methylthio)ethyl]guanidine

i. A mixture of 2-amino-4-chloromethylthiazole hydrochloride (9.0 g.)and cysteamine hydrochloride (5.53 g.) in acetic acid (100 ml.) washeated under reflux for 18 hours. The crude product obtained afterconcentration was treated with picric acid in ethanol to afford2-amino-4-[(2-aminoethyl)thiomethyl]thiazole dipicrate, m.p.approximately 200°-210° (from ethanol).

ii. The picrate was converted into the free base by addition ofhydrochloric acid, removal of picric acid by toluene extraction,basification with potassium carbonate and extraction of the aqueousresidue with ethanolether. Reaction of the base (1.89 g.) with methylisothiocyanate (0.73 g.) in ethanol (10 ml.) in the usual way gave thecrude thiourea. Chromatography on a column of silica gel with ethylacetate as eluant, followed by recrystallisation from isopropylalcholisopropyl acetate gaveN-methyl-N'-[2-((2-amino-4-thiazolyl)methylthio)ethyl]thiourea (1.0 g.),m.p. 136°-140°.

iii. Reaction ofN-methyl-N'-[2-((2-amino-4-thiazolyl)methylthio)ethyl]thiourea with leadcyanamide by the procedure of Example 3(b) gives the title compound.

EXAMPLE 115

The following hydroxymethyl and halomethyl thiazoles are converted tothe corresponding (2-aminoethyl)thiomethylthiazoles by the procedure ofExample 1:

2-hydroxymethyl-4-methylthiazole

4-chloromethyl-2-methylthiazole

2-chloro-4-chloromethylthiazole

2-bromomethyl-4,5-dimethylthiazole

4-ethyl-2-hydroxymethyl-5-methylthiazole and using the(2-aminoethyl)thiomethylthiazoles as starting materials in the procedureof Example 3 gives the following products, respectively:

N-cyano-N'-methyl-N"-[2-((4-methyl-2-thiazolyl)-methylthio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((2-methyl-4-thiazolyl)methylthio)ethyl]guanidine

N-[2-((2-chloro-4-thiazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((4,5-dimethyl-2-thiazolyl)methylthio)ethyl]guanidine

N-cyano-N'-[2-((4-ethyl-5-methyl-2-thiazolyl)methylthio)ethyl]-N"-methylguanidine.

Reacting 2-hydroxymethylthiazole with 3-mercaptopropylamine by theprocedure of Example 1 and using the resulting2-[(3-aminopropyl)thiomethyl]thiazole as the starting material in theprocedure of Example 3(a) givesN-cyano-N'-methyl-N"-[3-(2-thiazolylmethylthio)propyl]-guanidine.

EXAMPLE 116

2-Benzyl-4-thiazolecarboxylic acid is converted to the methyl ester andthe ester is reduced with lithium aluminium hydride in tetrahydrofuranto give 2-benzyl-4-hydroxymethylthiazole. By the procedure of Example 1this compound is converted to4-[(2-aminoethyl)thiomethyl]-2-benzylthiazole. Using this compound asthe starting material in the procedure of Example 110 givesN-[2-((2-benzyl-4-thiazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.

By the same procedure, from the following compounds:

2,4-thiazoledicarboxylic acid

2-hydroxy-4-thiazolecarboxylic acid the following products are obtained,respectively:

2,4-bis-[2-(N-cyano-N'-methylguanidino)ethylthiomethyl]thiazole

N-cyano-N'-[2-((2-hydroxy-4-thiazolyl)methylthio)ethyl]-N"-methylguanidine.

Reduction of 5-bromo-4-methyl-2-thiazolecarboxylic acid with diboraneyields 5-bromo-4-methyl-2-hydroxymethylthiazole which by the aboveprocedures may be converted toN-[2-((5-bromo-4-methyl-2-thiazolyl)-methylthio)ethyl]-N'-cyano-N"-methylguanidine.

EXAMPLE 117 N-Cyano-N'-methyl-N"-[3-(4-thiazolylmethoxy)propyl]guanidine

Using 4-chloromethylthiazole, prepared by reacting4-hydroxymethylthiazole with thionyl chloride, as the starting materialin the procedure of Example 22 gives the title compound.

EXAMPLE 118N-Cyano-N'-methyl-N"-[2-(2-(4-thiazolyl)ethyl)thioethyl]-guanidine

Using 4-(2-chloroethyl)thiazole as the starting material in theprocedure of Example 17 gives the title compound.

EXAMPLE 119

Using 2-[(2-aminoethyl)thiomethyl]thiazole as the starting material inthe procedure of Example 18 givesN-cyano-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine.

Treatment of the product with maleic acid in ethanol gives the maleatesalt.

EXAMPLE 120

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(2-thiazolyl-                                         methylthio)ethyl]guanidine                                                                              150 mg.                                             Sucrose                   75 mg.                                              Starch                    25 mg.                                              Talc                      5 mg.                                               Stearic aicd              2 mg.                                               ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 121N-Cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-N"methylguanidine

a. i. A solution was prepared by the gradual addition of cysteaminehydrochloride (2.03 g.) to sodium (0.83 g.). dissolved in ethanol (50ml.) with stirring at 0° under a nitrogen atmosphere. After stirring for2 hours at 0°, 3-bromoethylisothiazole (3.2 g.) was added dropwise over15 minutes at 0°, the reaction mixture subsequently being set asideovernight at room temperature. Following acidification to pH 3.5 withhydrochloric acid, concentration and re-evaporation with ethanol, theresidue was dissolved in ethanol, filtered and concentrated to yield3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g.). This wasconverted directly to the free base by treatment with aqueous potassiumcarbonate and extraction with ether. The extracts were dried overmagnesium sulphate, filtered and concentrated to yield the amine base asan oil (1.56 g.). The amine was dissolved in ethanol (10 ml.), methylisothiocyanate (0.66 g.) added, and the solution heated under reflux for30 minutes. Concentration, followed by purification of the crude productby chromatography on a column of silica gel with ethyl acetate as eluantfollowed by chromatography on a column of alumina with benzene/ethylacetate as eluant gaveN-methyl-N'-[2-(3isothiazolylmethylthio)ethyl]thiourea. (Found: C, 38.9;H, 5.4; N, 16.5; S, 38.3. C₈ H₁₃ N₃ S₃ requires: C, 38.8; H, 5.3; N,17.0; S, 38.9.

ii. Lead cyanamide (52.6 g.) was added to a solution ofN-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea (17.7 g.) inacetonitrile (500 ml.) containing dimethylformamide (50 ml.). Themixture was stirred under reflux for 48 hours, then filtered andconcentrated. The product was chromatographed on silica gel with ethylacetate as eluant and recrystallised from isopropyl acetate-ether togive N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-N"-methylguanidine,in a crystalline form, m.p. 63°-64°. Further recrystallisation fromisopropyl acetate afforded the cyanoguanidine in a crystalline form,m.p. 91°-92°. (Found: C, 42.6; H, 5.2; N, 27.4; S, 25.4. C₉ H₁₃ N₅ S₂requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).

b. i. The reaction of dimethyl-N-cyanoimidodithiocarbonate (1.50 g.)with 3-[(2-aminoethyl)thiomethyl]isothiazole (1.70 g.) by the proceduredescribed in Example 3(c) affordedN-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea.Recrystallisation from isopropyl acetate afforded 0.68 g., m.p. 85°-87°.(Found: C, 39.7; H, 4.4; N, 20.6; S, 35.4. C₉ H₁₂ N₄ S₃ requires: C,39.7; H, 4.4; N, 20.6; S, 35.3).

ii. The reaction ofN-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea (0.27g.) with excess methylamine according to the procedure described inExample 3(c) and recrystallisation of the product from ispropyl acetateaffordedN-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-N"-methylguanidine (0.12g.), m.p. 91°-93°. (Found: C, 42.4; H, 5.1; N, 27.3; S, 25.2. C₉ H₁₃ N₅S₂ requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).

EXAMPLE 122

The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g.) withcysteamine (from cysteamine hydrochloride, 3.76 g.) was performed underconditions similar to those described in Example 121. From the reactionthere was obtained 4-bromo-3-[2-aminoethyl)thiomethyl]isothiazolehydrobromide, which, following recrystallisation from ethanol-ether andacetonitrile, gave needles (4.05 g.) m.p. 111°-112°. The amine base(2.73 g.) was isolated by basification with sodium hydroxide andextraction with chloroform and then dissolved in ethanol and treatedwith methyl isothiocyanate (0.78 g.) The solution was heated underreflux for 30 minutes, concentrated and the residue triturated withether to yield the crystalline thiourea (2.9 g.) m.p. 60°-61°.Recrystallisation from isopropyl acetate gaveN-methyl-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]thiourea (2.3g.) as needles, m.p. 62°-63°.

Reaction ofN-methyl-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]thiourea wtihlead cyanamide by the procedure of Example 121 givesN-cyano-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]-N"-methylguanidine.

Hydrolysis of the above product according to the procedure of Example3(e) givesN-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]-N'-methylguanidinehydrochloride.

EXAMPLE 123

Reacting 4-hydroxymethyl-3-methylisothiazole (3.0 g.) with cysteaminehydrochloride (2.8 g.) in 48% aqueous hydrobromic acid (50 ml.) by theprocedure of Example 1 gives3-methyl-4-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide. Treatmentof this intermediate with aqueous potassium carbonate, extracting withchloroform, drying the chloroform extract over magnesium sulphate andconcentrating gives the free base, 5.0 g. of which is then reacted withmethyl isothiocyanate (1.94 g.) in ethanol (25 ml.) under reflux for 30minutes. The product is purified on a column of alumina and elution withbenzene givesN-methyl-N'-[2-((3-methyl-4-isothiazolyl)methylthio)ethyl]thiourea.Reaction of this product by the procedure of Example 121 givesN-cyano-N'-methyl-N"-[2-((3-methyl-4-isothiazolyl)methylthio)ethyl]guanidine.

Using the following halomethylisothiazoles as starting materials in theabove procedure:

3-bromomethyl-5-chloroisothiazole

4-bromo-5-chloromethyl-3-methylisothiazole the following products areobtained, respectively:

N-[2-((5-chloro-3-isothiazolyl)methylthio)ethyl]N'-cyano-N"-methylguanidine

N-[2-((4-bromo-3-methyl-5-isothiazolyl)methylthio)-ethyl]-N'-cyano-N"-methylguanidine.

Using in the above procedure, 3-mercaptopropylamine in place ofcysteamine, the product obtained isN-cyano-N'-methyl-N"-[3-((3-methyl-4-isothiazolyl)methylthio)-propyl]guanidine.

EXAMPLE 124 2-(3-Isothiazolylmethylthio)ethylguanidine sulphate

Reacting 3-[(2-aminoethyl)thiomethyl]isothiazole withS-methylisothiouronium sulphate by the procedure of Example 1 gives thetitle compound.

EXAMPLE 125

Reacting 3-[(2-aminoethyl)thiomethyl]isothiazole withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-[2-(2-isothiazolylmethylthio)ethyl]-N'-nitroguanidine and reaction ofthe same starting material with N,S-dimethyl-N'-nitroisothiourea by theprocedure of Example 2(iii) givesN-[2-(3-isothiazolylmethylthio)ethyl]-N'-methyl-N"-nitroguanidine.

Example 126

ReactingN-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea,prepared from 3-[(2-aminoethyl)thiomethyl]isothiazole by the procedureof Example 3(c) (i), with ethylamine by the procedure of Example 4 givesN-cyano-N'-ethyl-N"-ethyl-N"-[2-(3-isothiazolylmethylthio)ethyl]guanidine.

By the same procedure, using propylamine and2-(dimethylamino)ethylamine, the products are, respectively,N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-N"-propylguanidine andN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-isothiazolylmethylthio)ethyl]guanidine.

EXAMPLE 127

3,5-Dimethyl-4-isothiazolecarboxylic acid is converted to the methylester and the ester is reduced with lithium aluminium hydride intetrahydrofuran to give 4-hydroxymethyl-3,5-dimethylisothiazole.Treating this hydroxymethyl compound with thionyl bromide gives4-bromomethyl-3,5-dimethylisothiazole which is used as the startingmaterial in the procedure of Example 121 to giveN-cyano-N'-methyl-N"-[2-((3,5-dimethyl-4-isothiazolyl)-methylthio)ethyl]guanidine.

By the same procedure, using 3,5-isothiazoledicarboxylic acid, theproduct is3,5-bis-[2-(N-cyano-N'-methylguanidino)ethylthiomethyl]isothiazole.

EXAMPLE 128N-Cyano-N'-[3-(3-isothiazolylmethoxy)propyl]-N"-methylguanidine

Using 3-bromomethylisothiazole as the starting material in the procedureof Example 22 gives the title compound.

EXAMPLE 129N-Cyano-N'-[2-(2-(3-isothiazolyl)ethyl)thioethyl]-N"-methylguanidine

3-Isothiazoleacetic acid is esterified and the ester is reduced withlithium aluminium hydride in tetrahydrofuran to give3-(2-hydroxyethyl)isothiazole. Reacting this hydroxyethyl compound withthionyl chloride gives 3-(2-chloroethyl)isothiazole which is used as thestarting material in the procedure of Example 17 to give the titlecompound.

EXAMPLE 130

Using 3-[(2-aminoethyl)thiomethyl]isothiazole as the starting materialin Example 18 givesN-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]guanidine.

EXAMPLE 131

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-[2-(3-isothiazolylmethylthio)-                                     ethyl]-N"-methylguanidine 200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 132 N-Cyano-N'-methyl-N"-[3-(2-oxazolyl)thiopropyl]-guanidine

i. Hydrochloric acid (90 ml.) was added to potassium thiocyanate inethanol (1.8 l.) with stirring. Following filtration from inorganicmaterial, glycollaldehyde (35.9 g.) was added and the resulting solutionwas heated under reflux for 24 hours. Concentration, followed by coolingafforded a white solid which following recrystallisation from ethanolafforded oxazole-2-thiol (30 g.), m.p. 143°-4°.

ii. 3-Bromopropylphthalimide (13.4 g.) was added to a stirred solutionof sodium ethoxide (from 1.15 g. sodium and oxazole-2-thiol(5.1 g.) inethanol (100 ml.). The resultant solution was heated under reflux for2.5 hours and concentrated under reduced pressure. The residue wastriturated with water (100 ml.) to afford2-(3-phthalimidopropylthio)oxazole (14 g.) m.p. 101°. Recrystallisationfrom ethanol gave the pure oxazole, m.p. 102°-3°.

iii. Hydrazine hydrate (5.3 g.) was added carefully to a solution of2-(3-phthalimidopropylthio)oxazole (10 g.) in ethanol (173 ml.) withstirring. The solution was then heated under reflux for 25 minutes.After cooling, and filtration from phthalhydrazide, the filtrate wasconcentrated under reduced pressure and the residue was re-evaporatedwith ethanol to yield crude 2-(3-aminopropylthio)-oxazole which waswashed twice with ether and dissolved in ethanol (60 ml.). Methylisothiocyanate (2.54 g.) was added and the solution was heated underreflux for 30 minutes. Following cooling and filtration from insolublematerial, the filtrate was concentrated to an oil which waschromatographed on a column of silica gel with ethyl acetate as eluant.The product obtained crystallised from ethanol-ether-n-hexane to giveN-methyl-N'-[3-(2-oxazoylyl)-thiopropyl]thiourea (2.4 g.), m.p. 43°-45°.

Reaction of N-methyl-N'-[3-(2-oxazolyl)thiopropyl]-thiourea with leadcyanamide by the procedure of Example 121 gives the title compound.

EXAMPLE 133N-Cyano-N'-methyl-N"-[3-(4-methyl-2-oxazolyl)thiopropyl]-guanidine

The reaction of 4-methyloxazole-2-thiol (5.8 g.) with3-bromopropylphthalimide (13.4 g.) using the conditions described inExample 132 afforded 4-methyl-2-(3-phthalimidopropylthio)oxazole (14 g.)m.p. 92°-93° (ethanol-ether).

Treatment of the phthalimide compound (3.0 g.) with hydrazine (1.53 g.)followed by reaction of the product directly with methyl isothiocyanate(0.73 g.) using the conditions described in Example 132 affordedN-methyl-N'-[3-(4-methyl-2-oxazolyl)thiopropyl]thiourea (1.0 g.) m.p.73°-74° (from ethanol-ether-n-hexane).

Reaction of N-methyl-N'-[3-(4-methyl-2-oxazolyl)-thiopropyl]thioureawith lead cyanamide by the procedure of Example 121 gives the titlecompound.

EXAMPLE 134

Using the following 2-(chloroethyl)oxazoles as starting materials in theprocedure of Example 17:

5-(2-chloroethyl)-4-methyloxazole

5-(2-chloroethyl)-4-trifluoromethyloxazole the products are,respectively:

N-cyano-N'-methyl-N"-[2-(2-(4-methyl-5-oxazolyl)ethyl)-thioethyl]guanidine

N-cyano-N'-methyl-N"-[2-(2-(4-trifluoromethyl-5-oxazolyl)-ethyl)ethioethyl]guanidine.

Also, using 2-amino-5-(2-chloroethyl)oxazole, prepared by reacting2-amino-5-(2-hydroxyethyl)oxazole with thionyl chloride, in theprocedure of Example 17 givesN-[2-(2-amino-5-oxazolyl)ethyl)thioethyl]-N'-cyano-N"-methylguanidine.

EXAMPLE 135

Methyl 5-benzyl-4-oxazolecarboxylate is reduced with lithium aluminiumhydride in tetrahydrofuran to give 5-benzyl-4-hydroxymethyloxazole,which by reacting with thionyl chloride is converted to5-benzyl-4-chloromethyloxazole.

Using 5-benzyl-4-chloromethyloxazole as the starting material in theprocedure of Example 1(i)(b) gives4-[2-aminoethyl)thiomethyl]-5-benzyloxazole.

Using the above prepared intermediate as the starting material in theprocedure of Example 3(d) givesN-[2-((5-benzyl-4-oxazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.

Also, esterifying the following carboxylic acids and using the esters inthe procedure described above:

2.5-dimethyl-4-oxazolecarboxylic acid

4,5-oxazoledicarboxylic acid the products are, respectively:

N-cyano-N'-[2-((2,5-dimethyl-4-oxazolyl)methylthio)ethyl]-N"-methylguanidin

4,5-bis-[2-(N-cyano-N'-methylguanidino)ethylthiomethyl]oxazole.

Reacting 4-chloromethyl-2,5-dimethyloxazole, prepared from thecorresponding carboxylic acid as described above, with3-mercaptopropylamine by the procedure of Example 1(i)(b) and using theresulting 4-[(3-aminopropyl)thiomethyl]-2,5-dimethyloxazole as thestarting material in the procedure of Example 3(d) givesN-cyano-N'-[3-((2,5-dimethyl-4-oxazolyl)-methylthio)propyl]-N"-methylguanidine.

Reduction of 5-chloro-2-methyl-4-oxazolecarboxylic acid with diborane,conversion of the resultant hydroxymethyl compound to5-chloro-4-chloromethyl-2-methyloxazole and using this chloromethylcompound as the starting material gives, by the procedure of Example1(i)(b) and 3(d),N-[2-((5-chloro-2-methyl-4-oxazolyl)methylthio)ethyl]-N'-cyano-N"-methyl-guanidine.

EXAMPLE 136

Reacting 2-(3-aminopropylthio)oxazole withdimethyl-N-cyanoimidodithiocarbonate by the procedure of Example 3(c)(i)gives N-cyano-N'-[3-(2-oxazolyl)thiopropyl]-S-methylisothiourea.Reacting this intermediate with ethylamine by the procedure of Example 4gives N-cyano-N'-ethyl-N"-[3-(2-oxazolyl)thiopropyl]guanidine.

Using 2-(dimethylamino)ethylamine in place of ethylamine givesN-cyano-N'-(2-dimethylaminoethyl)-N"-[3-(2-oxazolyl)thiopropyl]guanidine.

EXAMPLE 137 3-(2-Oxazolyl) thiopropylguanidine

Reacting 2-83-aminopropylthio)oxazole with S-methylisothiourea by theprocedure of Example 1 gives the title compound.

EXAMPLE 138

Reacting 2(3-aminopropylthio)oxazole with S-methyl-N-nitroisothiourea bythe procedure of Example 2(ii) givesN-nitro-N'-3-(2-oxazolyl)thiopropyl]-guanidine. Similarly, reaction ofthe same starting material with N,S-dimethyl-N'-nitroisothiourea by theprocedure of Example 2(iii) givesN-methyl-N'-nitro-N"-[3-(2-oxazolyl)thiopropyl]guanidine.

EXAMPLE 139N-Cyano-N'-methyl-N"-[3-((5-methyl-4-oxazolyl)methoxy)propyl[guanidine

Using 4-chloromethyl-5-methyloxazole as the starting material in theprocedure of Example 22 gives the title compound.

EXAMPLE 140

Using 2-(3-aminopropylthio)oxazole as the starting material in theprocedure of Example 18 givesN-cyano-N'-[3-(2-oxazolyl)thiopropyl]guanidine.

EXAMPLE 141

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[3-(4-methyl-2-                                          oxazolyl)thiopropyl]guanidine                                                                           200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 142

a. A solution of 3-chloromethylisoxazole (5.8 g.) and cysteaminehydrochloride (6.25 g.) in aqueous hydrobromic acid (48%, 100 ml) washeated under reflux for 6 hours. Concentration in the presence of waterand subsequently n-propanol, followed by recrystallisation of theresidue from isopropyl alcohol-ethanol afforded3-[(2-aminoethyl)thiomethyl]isoxazole hydrobromide, m.p. 131°-133°.(Found: Br,33.6;S, 13.7.C₆ H₁₀ N₂ OS. H Br requires: Br, 33.4; S, 13.4).

b. A solution of 3-[(2-aminoethyl)thiomethyl]isoxazole (2.44 g.)extracted from the hydrobromide and potassium carbonate withether-ethanol (3:1) and methyl isothiocyanate (1.36 g.) in absoluteethanol (40 ml.) was heated under reflux for 1.5 hours. Concentrationfollowed by chromatographic purification on a column of silica gel withether as eluant affordedN-methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea as a colourlessoil (2.5 g.). (Found: C, 41.3: H, 6.2; N,18.2; S, 27.3. C₈ H₁₃ N₂ O₂ Srequires: C, 41.5; H, 5.7; N, 18.2; S, 27.7).

C. Reaction of N-methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thioureawith lead cyanamide by the procedure of Example 121 givesN-cyano-N'-methyl-N"-[2-(2-(3-isoxazolylmethylthio)ethyl]guanidine.

Hydrolysis of the last prepared compound according to the procedure ofExample 3(e) givesN-methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]guanidine hydrochloride.

EXAMPLE 143

Using the following chloromethylisoxazoles (prepared from thecorresponding hydroxymethylisoxazoles by treatment thereof with thionylchloride) as starting materials in the procedure of Example 142:

3-chloromethyl-5-methylisoxazole

3-bromo-5-chloromethylisoxazole

4-chloromethyl-3,5-dimethylisoxazole

4(2-chloroethyl)-5-methylisoxazole the products are, respectively:

N-cyano-N'-methyl-N"-[2-(5-methyl-3-isoxazolylmethylthio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-(3-bromo-5-isoxazolylmethylthio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-(3,5-dimethyl-4-isoxazolylmethylthio)ethyl]guanidin

N-cyano-N'-methyl-N"-[2-(2-(5-methyl-4-isoxazolyl)ethylthio)ethyl]guanidine.

EXAMPLE 144

Using in the procedure of Example 142, 3-mercaptopropylamine in place ofcysteamine the product isN-cyano-N'-methyl-N"-[3-(3-isoxazolylmethylthio)-propyl]guanidine.

EXAMPLE 145

Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole withS-methyl-isothiourea by the procedure of Example 1 gives[2-(3-isoxazolylmethylthio)ethyl]guanidine.

EXAMPLE 146

By the procedure of Example 22, 3-chloromethylisoxazole is used as thestarting material to giveN-cyano-N'-[2-(3-isoxazolylmethoxy)ethyl]-N"-methylguanidine.

EXAMPLE 147

3-[(2-Aminoethyl)thiomethyl]isoxazole is used as the starting materialin the procedure of Example 18 to giveN-cyano-N'[2-(3-isoxazolylmethylthio)ethyl]-guanidine.

EXAMPLE 148

Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole withdimethyl-N-cyanoimidodithiocarbonate by the procedure of Example 3(c)(i)gives N-cyano-N'-[2-(3-isoxazolylmethylthio)ethyl]-S-methylisothiourea.Reacting this intermediate with the following amines by the procedure ofExample 4:

ethylamine

propylamine

2-(dimethylamino)ethylamine gives the following products, respectively:

N-cyano-N'-ethyl-N"-[2-(3-isoxazolylmethylthio)ethyl]guanidine

N-cyano-N'-propyl-N"-[2-(3-isoxazolylmethylthio)ethyl]guidine

N-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-isoxazolylmethylthio)ethyl]guanidine.

EXAMPLE 149

Reacting 3-[(2-aminoethyl)thiomethyl]isoxazole withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(3-isoxazolylmethylthio)ethyl]guanidine.

Similarly, reaction of the same starting material withN,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii)gives N-methyl-N'-nitro-N"-[2-(3-isoxazolylmethylthio)ethyl]guanidine.

EXAMPLE 150

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-                                                         [2-(3-isoxazolylmethylthio)-                                                  ethyl]thiourea            200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atoms shown a five membered unsaturated heterocyclicring having one nitrogen atom, one sulphur or oxygen and three carbonatoms, said unsaturated heterocyclic ring being thiazole, isothiazole,oxazole or isoxazole, and Y is NH are exemplified by the followingexamples.

EXAMPLE 151

Reacting 2-hydroxymethylthiazole with thionyl chloride, then using theresulting 2-chloromethylthiazole as the starting material in theprocedure of Example 34 gives 2-(2-thiazolymethylamino)ethylguanidinesulphate.

Similarly, from 4-hydroxymethylthylthiazole,2-(4-thiazolylmethylamino)ethylguanidine sulphate is prepared.

EXAMPLE 152

a. Reacting ethylenediamine with 2-chloromethylthiazole, by theprocedure of Example 34 gives N-(2-thiazolylmethyl)ethylenediamine.Reacting this intermediate with S-methyl-N-nitroisothiourea by theprocedure of Example 2(ii) givesN-nitro-N'-[2-(2-thiazolylmethylamino)ethyl]guanidine. Treatment withhydrobromic acid gives the hydrobromide salt.

b. Similarly, reaction of the same intermediate withN,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii)gives N-methyl-N'-nitro-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine.

EXAMPLE 153

Reacting ethylenediamine with 2-chloromethylthiazole by the procedure ofExample 34, then reacting the resultingN-(2-thiazolylmethyl)ethylenediamine withN-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a), givesN-cyano-N'-methyl-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine.Hydrolysis of this compound by the procedure of Example 3(e) givesN-methyl-N'-[2-(2-thiazolylmethylamino)ethyl]-guanidinetrihydrochloride.

EXAMPLE 154

Using, in the procedure of Example 153.N-(4-thiazolylmethyl)ethylenediamine (prepared by treating4-hydroxymethylthiazole with thionyl, chloride and reacting theresulting 4-chloromethylthiazole with ethylenediamine by the procedureof Example 34),N-cyano-N'-methyl-N"-[2-(4-thiazolylmethylamino)ethyl]guanidine isprepared.

Similarly, from 5-hydroxymethylthiazole,N-cyano-N'-methyl-N"-[2-(5-thiazolylmethylamino)ethyl]-guanidine isprepared.

EXAMPLE 155

Reacting N-(2-thiazolylmethyl)ethylenediamine with ethyl isothiocyanateby the procedure of Example 3(b) and then chromatographing givesN-ethyl-N'-[2-(2-thiazolylmethylamino)ethyl]thiourea. Reacting thisthiourea with lead cyanamide by the procedure of Example 3(b) givesN-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylamino)ethyl]-guanidine.

Using 2-dimethylaminoethyl isothiocyanate in place of ethylisothiocyanate in the above procedure givesN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine.

EXAMPLE 156

Using, in the procedure of Example 153, the following haloalkylthiazoles(which may be prepared by treating the hydroxyalkylthiazoles with athionyl halide):

2-amino-4-chloromethylthiazole

2-chloromethyl-4-methylthiazole

2-chloro-4-chloromethylthiazole

2-bromomethyl-4,5-dimethylthiazole

2-chloromethyl-4-ethyl-5-methylthiazole the products are, respectively:

N-[2-((2-amino-4-thiazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((4-methyl-2-thiazolyl)-methylamino)ethyl]guanidine

N-[2-((2-chloro-4-thiazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((4,5-dimethyl-2-thiazolyl)-methylamino)ethyl]guanidine

N-cyano-N'-[2-((4-ethyl-5-methyl-2-thiazolyl)methylamino)ethyl]-N'-methylguanidine.

Also, using as starting materials in the procedure of Example 153, thefollowing chloromethylthiazoles (which may be prepared by converting thecorresponding thiazolecarboxylic acid compounds to thehydroxymethylthiazoles by the procedure of Example 116 and then treatingthe hydroxymethylthiazoles with thionyl chloride):

2-benzyl-4-chloromethylthiazole

2,4-di(chloromethyl)thiazole

5-bromo-2-chloromethyl-4-methylthiazole

4-chloromethyl-2-hydroxythiazole the products are, respectively:

N-[2-((2-benzyl-4-thiazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

2,4-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl[thiazole

N-[2-((5-bromo-4-methyl-2-thiazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-[2-((2-hydroxy-4-thiazolyl)methylamino)ethyl]-N"-methylguanidine

Using, in the procedure of Example 153, 1.3-diaminopropane in place ofethylenediamine, the product isN-cyano-N"-methyl-N"-[3-(2-thiazolylmethylamino)propyl]guanidine.

EXAMPLE 157 N-Cyano-N'-methyl-N"-[3-(2-thiazolylamino)propyl]-guanidine

Using 2-aminothiazole as the starting material in the procedure ofExample 40 gives the title compound.

EXAMPLE 158

Using 2-(3-aminopropylamino)thiazole as the starting material in theprocedure of Example 18 givesN-cyano-N'-[3-(2-thiazolylamino)propyl)guanidine.

EXAMPLE 159

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(2-thiazolyl-                                         methylamino)ethyl]guanidine                                                                             200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule

EXAMPLE 160 2-(3-Isothiazolylmethylamino)ethylguanidine sulphate

By the procedure of Example 34, ethylenediamine is reacted with3-bromomethylisothiazole to giveN-(3-isothiazolylmethyl)ethylenediamine. This intermediate is heatedunder reflux with S-methylisothiouronium sulphate in water for 3 hoursby the procedure of Example 1 to give the title compound.

EXAMPLE 161

Reaction of N-(3-isothiazolylmethyl)ethylenediamine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-[2-(3-isothiazolylmethylamino)-ethyl]-N'-nitroguanidine.

Similarly, reaction of the same starting material withN,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii)gives N-[2-(3-isothiazolylmethlamino)ethyl]-N'-methyl-N"-nitroguanidine.

EXAMPLE 162

Reaction of 3-bromomethylisothiazole with ethylenediamine by theprocedure of Example 34 and reaction of the resultingN-(3-isothiazolylmethyl)ethylenediamine with methyl isothiocyanate bythe procedure of Example 3(b) and then chromatographing givesN-methyl-N'-[2-(3-isothiazolylmethylamino)ethyl]thiourea. Thisintermediate is reacted with lead cyanamide by the procedure of Example3(b) to giveN-cyano-N'-[2-(3-isothiazolylmethylamino)ethyl]-N"-methylguanidine.Hydrolysis of the last prepared compound by the procedure of Example3(e) gives N-[2-(3-isothiazolylmethylamino)ethyl]-N'-methylguanidinedihydrochloride.

EXAMPLE 163

Using ethyl isothiocyanate in place of methyl isothiocyanate in theprocedure of Example 162 givesN-cyano-N'-ethyl-N"-[2-(3-isothizolylmethylamino)ethyl]guanidine.

By the same procedure, using 2-dimethylaminoethyl isothiocyanate.N-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-isothiazolylmethylamino)ethyl]guanidineis prepared.

EXAMPLE 164

Using, in the procedure of Example 162, the followinghaloalkylisothiazoles:

4-bromo-3-bromomethylisothiazole

3-bromomethyl-5-chloroisothiazole

4-bromo-5-chloromethyl-3-methylisothiazole

4-chloromethyl-3-methylisothiazole

4-bromomethyl-3,5-dimethylisothiazole

3,5-di(bromomethyl)isothiazole

3-(2-chloroethyl)isothiazole the products are, respectively:

N-[2-((4-bromo-3-isothiazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidin

N-[2-((5-chloro-3-isothiazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-[2-((4-bromo-3-methyl-5-isothiazolyl)methylamino)-ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-((3-methyl-4-isothiazolyl)methylamino)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((3,5-dimethyl-4-isothiazolyl)methylamino)ethyl]guanidine

3,5-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]isothiazole

N-cyano-N'-[2-(2-(3-isothiazolyl)ethyl)aminoethyl]-N"-methylguanidine.

Using, in the procedure of Example 162, 1,3-diaminopropane in place ofethylenediamine, the product isN-cyano-N'-[3-(3-isothiazolylmethylamino)-propyl]-N"-methylguanidine.

EXAMPLE 165

Using 3-aminoisothiazole as the starting material in the procedure ofExample 40 gives 3-(3-amino-propylamino)isothiazole.

Using 3-(3-aminopropylamino)isothiazole as the starting material in theprocedure of Example 3 givesN-cyano-N'-[3-(3-isothiazolylamino)propyl]-N"-methylguanidine.

EXAMPLE 166

Using 3-(3-aminopropylamino)isothizole as the starting material in theprocedure of Example 18 givesN-cyano-N'-[3-(3-isothiazolylamino)propyl]guanidine.

EXAMPLE 167

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-[2-(3-isothiazolyl-                                                methylamino)ethyl]-N"-methyl-                                                 guanidine                 150 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 168

Using the following chloroethyloxazoles as starting materials in theprocedure of Example 34:

5-(2-chloroethyl)-4-methyloxazole

5-(2-chloroethyl)-4-trifluoromethyloxazole

2-amino-5-(2-chloroethyl)oxazole the following products are obtained,respectively:

2-[2-(4-methyl-5-oxazolyl)ethylamino]ethylguanidine

2-[2-(4-trifluoromethyl-5-oxazolyl)ethylamino]ethylguanidine

2-[2-(2-amino-5-oxazolyl)ethylamino]ethylguanidine.

EXAMPLE 169

5-Benzyl-4-oxazolecarboxylic acid is converted to5-benzyl-4-hydroxymethyloxazole by the procedure of Example 135.Treating this hydroxymethyl compound with thionyl chloride gives5-benzyl-4-chloromethyloxazole.

Reacting ethylenediamine with 5-benzyl-4-chloromethyloxazole by theprocedure of Example 34, then reacting the resultingN-(5-benzyl-4-oxazolylmethyl)ethylenediamine with methyl isothiocyanateby the procedure of Example 3(b) and chromatographing givesN-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-thiourea.Reacting this thiourea with lead cyanamide by the procedure of Example3(b) givesN-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.

By the same procedure, using the following compounds as the startingmaterials:

2,5-dimethyl-4-oxazolecarboxylic acid

4,5-oxazoledicarboxylic acid the following products are obtained,respectively:

N-cyano-N'-[2-((2,5-dimethyl-4-oxazolyl)methylamino)ethyl]-N"-methylguanidine

4,5-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]oxazole.

Reduction of 5-chloro-2-methyl-4-oxazolecarboxylic acid with diboraneand treatment of the resultant hydroxymethyl compound with thionylchloride gives 5-chloro-4-chloromethyl-2-methyloxazole which, by theabove procedure, is converted toN-[2-((5-chloro2-methyl-4-oxazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.

EXAMPLE 170

Using 5-chloromethyl-4-methyloxazole as the starting material, by theprocedures of Example 152(a) and (b).N-[2-((4-methyl-5-oxazolyl)methylamino)ethyl]-N'-nitroguanidine andN-methyl-N'-[2-((4-methyl-5-oxazolyl)methylamino)ethyl]-N"-nitroguanidineare prepared.

EXAMPLE 171

Reacting of 5-chloromethyl-4-methyloxazole with ethylenediamine by theprocedure of Example 34 and reaction of the resultingN-(4-methyl-5-oxazolylmethyl)ethylenediamine with ethyl isothiocyanateby the procedure of Example 3(b) gives, after purifying by columnchromatography,N-ethyl-N'-[2-(4-methyl-5-oxazolylmethylamino)ethyl]thiourea. Thisthiourea is reacted with lead cyanamide by the procedure of Example 3(b)to giveN-cyano-N'-ethyl-N"-[2-((4-methyl-5-oxazolyl)methylamino)ethyl]guanidine.

By the same procedure, using 2-dimethylaminoethyl isothiocyanate inplace of ethyl isothiocyanate,N-cyano-N'-(2-dimethylaminoethyl)-N"-[2-((4-methyl-5-oxazolyl)methylamino)ethyl]guanidineis prepared.

Using 1,3-diaminopropane in place of ethylendiamine and methylisothiocyanate in place of ethyl isothiocyanate in the above proceduregivesN-cyano-N'-methyl-N"-[3-((4-methyl-5-oxazolyl)methylamino)-propyl]guanidine.

EXAMPLE 172

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-[2-((4-Methyl-5-oxazolyl)methyl-                                            amino)ethyl]-N'-cyano-N"-methyl-                                              guanidine                 200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 173

Using, in the procedure of Example 153. the followingchloroalkylisoxazoles:

3-chloromethylisoxazole

3-chloromethyl-5-methylisoxazole

3-bromo-5-chloromethylisoxazole

4-chloromethyl-3,5-dimethylisoxazole

4-(2-chloroethyl)-5-methylisoxazole the products are, respectively:

N-cyano-N'-methyl-N"-[2-(3-isoxazolylmethylamino)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-(5-methyl-3-isoxazolylmethylamino)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-(3-bromo-5-isoxazolylmethylamino)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-(3,5-dimethyl-4-isoxazolylmethylmino)ethyl]guanidin

N-cyano-N'-methyl-N"-[2-(2-(5-methyl-4isoxazolyl)ethylamino)ethyl]guanidine.

EXAMPLE 174

Using in the procedure of Example 153,3-chloromethylisoxazole and1,3-diaminopropane as the starting materials, the product isN-cyano-N'-methyl-N"-[3-(3-isoxazolylmethylamino)propyl]guanidine.

EXAMPLE 175

3-Chloromethylisoxazole is used as starting material in the procedure ofExample 34 to give 2-(3-isoxazolylmethylamino)ethylguanidine.

EXAMPLE 176

By the procedure of Example 155, N-(3-isoxazolylmethyl)ethylenediamineis reacted with the following isothiocyanates:

ethyl isothiocyanate

propyl isothiocyanate

2-dimethylaminoethyl isothiocyanate and the resulting thioureaintermediates are reacted with lead cyanamide by the procedure ofExample 3(b) to give the following products, respectively:

N-cyano-N'-ethyl-N"-[2-(3-isoxazolylmethylamino)ethyl]guanidine

N-cyano-N'-propyl-N"-[2-(3-isoxazolylmethylamino)ethyl]guanidine

N-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-isoxazolylmethylamino)ethyl]guanidine.

EXAMPLE 177

Using 3-chloromethylisoxazole as the starting material, by theprocedures of Example 152(a) and (b),N-[2-(3-isoxazolylmethylamino)ethyl]-N'-nitroguanidine andN-[2-(3-isoxazolylmethylamino)ethyl]-N'-methyl-N"-nitroguanidine areprepared.

EXAMPLE 178

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(3-isoxazolyl-                                        methylamino)ethyl]guanidine                                                                             200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I where A is such that there is formed togetherwith the carbon atom shown a triazole ring and Y is oxygen or sulphur(sulphur is preferred) are exemplified by the following examples.

EXAMPLE 179 2-[3-(1,2,4-triazolyl)methylthio]ethylguanidine sulphate

By the procedure of Example1,3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole dihydrobromide. m.p.177°-179°, was prepared.

This amine salt is converted to the free base and reacted withS-methylisothiouronium sulphate by the procedure of Example 1 to givethe title compound.

EXAMPLE 180

Treatment of 3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole withdimethyl-N-cyanoimidodithiocarbonate and then with methylamine by theprocedure of Example 3(c) givesN-cyano-N'-methyl-N"-[2-(3-(1,2,4-triazolyl)methylthio)ethyl]guanidine.

Hydrolysis of this compound by the method of Example 3(e) givesN-methyl-N'-[2-(3-(1,2,4-triazolyl)methylthio)ethyl]guanidinedihydrochloride.

EXAMPLE 181 2-[4-Methyl-3-(1,2,4-triazolyl)methylthio]ethylguanidinesulphate

Ethoxyacetyl chloride (57 g.) was added slowly to a stirred solution of4-methylthiosemicarbazide (53.5 g.) in dry pyridine (500 ml.) at 0°-5°.The mixture was allowed to attain room temperature and stirring wascontinued for 18 hours. Following concentration under reduced pressurethe residue was treated with a solution of sodium (21.4 g.) in ethanol(500 ml.) and the mixture was heated under reflux for 24 hours.Following concentration and acidification with hydrochloric acid a solidwas obtained. After partial concentration the solid was collected andrecrystallized from ethyl acetate to give3-ethoxymethyl-4-methyl-1,2,4-triazoline-5-thione (53 g.), m.p.137°-138°. The thione (44 g.) was desulphurised by slow addition to asolution prepared from nitric acid (75 ml.) water (150 ml.) and sodiumnitrite (1.5 g.) at 15°-20°. Following subsequent basification withsodium carbonate and concentration the residue was extracted withethanol-ether 1:1 and distilled to afford 3-ethoxymethyl-4-methyl-1,2,4-triazole (30 g.) b.p. 154°-156°/0.05 mm. The abovecompound (15 g.) dissolved in 48% aqueous hydrobromic acid (150 ml.) washeated under reflux for 24 hours and concentrated to dryness to give3-hydroxymethyl-4-methyl-1,2,4-triazole.

Reaction of 3-hydroxymethyl-4-methyl-1,2,4-triazole with cysteaminehydrochloride and hydrobromic acid by the procedure of Example 1 gives3-[(2-aminoethyl)thiomethyl]-4-methyl-1,2,4-triazole dihydrobromide,m.p. 175°-177°.

The above prepared dihydrobromide salt is converted to the free base bythe procedure of Example 1. Reaction of3-[(2-aminoethyl)thiomethyl]-4-methyl-1,2,4-triazole withS-methylisothiouronium sulphate by the procedure of Example 1 gives thetitle compound.

EXAMPLE 1823,5-bis-[2-(N-Cyano-N'-methylguanidino)ethylthiomethyl]-1,2,4-triazole

i. The reaction of 3,5-dihydroxymethyl-1,2,4-triazole (9.0 g; obtainedfrom 1,2,4-triazole and excess formaldehyde at elevated temperatures)with cysteamine hydrochloride (17.3 g.) by the procedure described inExample 1 (i) (a) afforded3,5-bis-((2-aminoethyl)thiomethyl)-1,2,4-triazole trihydrobromide (4.7g.). m.p. 214°-215°.

ii. The reaction of3,5-bis((2-aminoethyl)thiomethyl)-1,2,4-triazole(from 6.5 g.trihydrobromide) with methyl isothiocyanate (1.93 g.) afforded thebis-thiourea which was purified by passage through a column of silicagel with ethanol as eluant. Trituration with isopropyl acetate, followedby recrystallization from ethanol-ether afforded3,5-bis-[2-(N-methylthioureido)ethylthiomethyl]-1,2,4-triazole (0.9 g.)m.p. 133°-135°.

iii. The reaction of3,5-bis-[2-(N-methylthioureido)ethylthiomethyl]-1,2,4-triazole with leadcyanamide by the procedure of Example 3(b) gives the title compound.

EXAMPLE 183

The reaction of 3-[(2-aminoethyl)thiomethyl]-4-methyl-1,2,4-triazolewith S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)ethyl]-N'-nitroguanidine.Reaction of the same starting material withN,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii)givesN-methyl-N'-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)ethyl]-N"-nitroguanidine.

EXAMPLE 184

By the procedure of Example 1, the following hydroxymethyl triazoles:

2-benzyl-3-hydroxymethyl-1,2,4-triazole

3-amino-5-hydroxymethyl-1,2,4-triazole

3-bromo-5-hydroxymethyl-1,2,4-triazole

1-benzyl-4-hydroxymethyl-1,2,3-trizole are converted to thecorresponding (2-aminoethyl)thiomethyl triazoles and these intermediatesare reacted with dimethyl-N-cyanoimidodithiocarbonate and methylamine bythe procedure of Example 3(c) to give the following products,respectively:

N-[2-(2-benzyl-3-(1,2,4-triazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

N-[2-(3-amino-5-(1,2,4-triazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

N-[2-(3-bromo-5-(1,2,4-triazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

N-[2-(1-benzyl-4-(1,2,3-triazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

EXAMPLE 185

Converting 5-methyl-4-(1,2,3-triazole)-carboxylic acid to the methylester and then reducing the ester with lithium aluminum hydride intetrahydrofuran gives 4-hydroxymethyl-5-methyl-1,2,3-triazole.

Converting 4-hydroxymethyl-5-methyl-1,2,3-triazole to4-[(2-aminoethyl)thiomethyl]-5-methyl-1,2,3, triazole by the procedureof Example 1 and using this intermediate as the starting material in theprocedure of Example 3 givesN-cyano-N'-methyl-N"-[2-(5-methyl-4-(1,2,3-triazolyl)methylthio)ethyl]guanidine.

By the same procedure, using the following ethyl triazolecarboxylatecompounds:

diethyl 4,5-(1,2,3-triazole)dicarboxylate ethyl3-hydroxy-5-(1,2,4-triazole)carboxylate (prepared by esterification ofthe corresponding acid)

ethyl 5-amino-4-(1,2,3-triazole)carboxylate ethyl5-hydroxy-4-(1,2,3-triazole)carboxylate the following products areobtained, respectively:

4,5-bis-[2-(N-cyano-N'-methylguanidino)ethylthiomethyl]-1,2,3-triazole

N-cyano-N'-[2-(3-hydroxy-5-(1,2,4-triazolyl)methylthio)ethyl]-N"-methylguanidine

N-[2-(5-amino-4-(1,2,3-triazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-[2-(5-hydroxy-4-(1,2,3-triazolyl)methylthio)ethyl]-N'-methylguanidine.

Reduction of 3-chloro-5-(1,2,4-triazole)-carboxylic acid with diboranegives the corresponding hydroxymethyl compound and, using this asstarting material in the above process, givesN-[2-(3-chloro-5-(1,2,4-triazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.

Reacting 4-hydroxymethyl-5-methyl-1,2,3-triazole with3-mercaptopropylamine by the procedure of Example 1 and using theresulting 4-[(3-aminopropyl)thiomethyl]-5-methyl-1,2,3-triazole as thestarting material in the procedure of Example 3 givesN-cyano-N'-methyl-N"-[3-(5-methyl-4-(1,2,3-triazolyl)methylthio)propyl]-guanidine.

EXAMPLE 186

Reaction of 3-[(2-aminoethyl)thiomethyl]-4-methyl-1,2,4-triazole withdimethyl-N-cyanoimidodithiocarbonate by the procedure of Example 3(c)(i)givesN-cyano-N'-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)ethyl]-S-methylisothiourea.Reaction of this intermediate with ethylamine by the procedure ofExample 4 givesN-cyano-N'-ethyl-N"-[2-(4-methyl-3(1,2,4-triazolyl)-methylthio)ethyl]guanidine.

Using propylamine in place of ethylamine givesN-cyano-N'-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)ethyl]-N"-propylguanidine.

EXAMPLE 187

Using 3-mercapto-1,2,4-triazole as the starting material in theprocedure of Example 20 givesN-cyano-N'-methyl-N"-[3-(3-(1,2,4-triazolyl)thio)propyl]-guanidine.

Using 4-mercapto-1,2,3-triazole, the product isN-cyano-N'-methyl-N"-[3-(4-(1,2,3-triazolyl)thio)propyl]guanidine.

EXAMPLE 188

Using 3-(2-chloroethyl)-1,2,4-triazole as the starting material in theprocedure of Example 17 givesN-cyano-N'-methyl-N"-[2-(2-(3-(1,2,4-triazolyl)ethyl)thioethyl]guanidine.

EXAMPLE 189N-Cyano-N'-methyl-N"-[3-(3-(1,2,4-triazolyl)methoxy)-propyl]guanidine

Using 3-chloromethyl-1,2,4-triazole as the starting material in theprocedure of Example 22 gives the title compound.

EXAMPLE 190

Using 3-[(2-aminoethyl)thiomethyl]-4-methyl-1,2,4-triazole as thestarting material in the procedure of Example 18 givesN-cyano-N'-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)ethyl]guanidine.

By the same procedure, using4-[(2-aminoethyl)thiomethyl]-5-methyl-1,2,3-triazole.N-cyano-N'-[2-(5-methyl-4-(1,2,3-triazolyl)methylthio)ethyl]guanidine isprepared.

EXAMPLE 191

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(3-(1,2,4-                                            triazolyl)methylthio)ethyl]guanidine                                                                    200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a triazole ring and Y is NH are exemplifiedby the following examples.

EXAMPLE 192 2-[3-(1,2,4-Triazolyl)methylamino]ethylguanidine sulphate

By the procedure of Example 34, ethylenediamine is reacted with3-chloromethyl-1,2,4-triazole to giveN-[3-(1,2,4-traiazolyl)methyl]ethylenediamine.

The above prepared compound is heated under reflux withS-methylisothiouronium sulphate in water for 3 hours by the procedure ofExample 1 to give the title compound.

EXAMPLE 193

Reacting N-[3-(1,2,4-triazolyl)methyl]-ethylenediamine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(3-(1,2,4-triazolyl)methylamino)ethyl]guanidine.

Treatment of the product with hydrobromic acid gives the hydrobromidesalt. Treatment of the same starting material withN,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii)givesN-methyl-N'-nitro-N"-[2-(3-(1,2,4-triazolyl)methylamino)ethyl]guanidine.

EXAMPLE 194

Treating 4-hydroxymethyl-5-methyl-1,2,3-triazole with thionyl chloridegives 4-chloromethyl-5-methyl-1,2,3-triazole. Reacting ethylenediaminewith 4-chloromethyl-5-methyl-1,2,3-triazole and reacting the resultingN-[5-methyl-4-(1,2,3-triazolyl)methyl]ethylenediamine withS-methylisothiouronium sulphate by the procedure of Example 1 gives2-[5-methyl-4-(1,2,3-triazolyl)methylamino]ethylguanidine sulphate.

Using N-[5-methyl-4-(1,2,3-triazolyl)methyl]ethylenediamine in theprocedure of Example 35 givesN-nitro-N'-[2-(5-methyl-4-(1,2,3-triazolyl)methylamino)-ethyl]guanidine.

EXAMPLE 195

Reacting 3-chloromethyl-1,2,4-triazole with ethylenediamine by theprocedure of Example 34, then reacting the resultingN-[3-(1,2,4-triazolyl)methyl]ethylenediamine with methyl isothiocyanateby the procedure of Example 3(b), then chromatographing givesN-methyl-N'-[2-(3-(1,2,4-triazolyl)methylamino)ethyl]-thiourea. Thisthiourea is reacted with lead cyanamide by the procedure of Example 3(b)to giveN-cyano-N'-methyl-N"-[2-(3-(1,2,4-triazolyl)methylamino)ethyl]guanidine.Hydrolysis of this compound by the procedure of Example 3(e) givesN-methyl-N'-[2-(3-(1,2,4-l -triazolyl)-methylamino)ethyl]-guanidinetrihydrochloride.

EXAMPLE 196

Ethylenediamine is reacted with 4-chloromethyl-5-methyl-1,2,3-triazoleby the procedure of Example 34 and the resultingN-[5-methyl-4-(1,2,3-triazolyl)methyl]-ethylenediamine is reacted withmethyl isothiocyanate by the procedure of Example 3(b) to give, afterchromatographing,N-methyl-N'-[2-(5-methyl-4-(1,2,3-triazolyl)methylamino)ethyl]thiourea.This thiourea is reacted with lead cyanamide by the procedure of Example3(b) to giveN-cyano-N'-methyl-N"-[2-(5-methyl-4-(1,2,3-triazolyl)-methylamino)ethyl]-guanidine.

Using ethyl isothiocyanate is place of methyl isothiocyanate in theabove procedure givesN-cyano-N'-ethyl-N"-[2-(5-methyl-4-(1,2,3-triazolyl)methylamino)ethyl]guanidine.

EXAMPLE 197

Using 2-dimethylaminoethyl isothiocyanate in place of methylisothiocyanate in the procedure of Example 196 givesN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(5-methyl-4-(1,2,3-triazolyl)methylamino)ethyl]guanidine.

Using in the procedure of Example 196,N-[3-(1,2,4-triazolyl)methyl]ethylenediamine and 2-dimethylaminoethylisothiocyanate givesN-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-(1,2,4-triazolyl)methylamino)ethyl]guanidine.

EXAMPLE 198

Using, in the procedure of Example 195, the followingchloroalkyltriazoles (which may be prepared by treating thecorresponding hydroxyalkyltriazoles with thionyl chloride):

3-(2-chloroethyl)-1,2,4-triazole

3-cloromethyl-4-methyl-1,2,4-triazole

3,5-di(chloromethyl)-1,2,4-triazole

3-chloromethyl-2-benzyl-1,2,4-triazole

3-amino-5-chloromethyl-1,2,4-triazole

3-bromo-5-chloromethyl-1,2,4-triazole the products are, respectively:

N-cyano-N'-methyl-N"-[2-(2-(3-(1,2,4-triazolyl))ethylamino)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-(4-methyl-3-(1,2,4-triazolyl)methylamino)ethyl]guanidine

3,5-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]-1,2,4-triazole

N-[2-(2-benzyl-3-(1,2,4-triazolyl)mthylamino)ethyl]-N'-cyano-N"-methylguanidine

N-[2-(3-amino-5-(1,2,4-triazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-[2-(3-bromo-5(1,2,4-triazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.

Using in the procedure of Example 195, 1,3-diaminopropane in place ofethylenediamine, the product isN-cyano-N'-methyl-N"-[3-(3-(1,2,4-triazolyl)methylamino)propyl]guanidine.

EXAMPLE 199

Using in the procedure of Example 195, the followingchloroalkyltriazoles, prepared from the corresponding hydroxyalkylcompounds by reacting with thionyl chloride:

1-benzyl-4-chloromethyl-1,2,3-triazole

4-chloromethyl-5-methyl-1,2,3-triazole

5-amino-4-chloromethyl-1,2,3-triazole

4-chloromethyl-5-hydroxy-1,2,3-triazole

4,5-di(chloromethyl)-1,2,3-triazole

3-chloro-5-chloromethyl-1,2,4-triazole

3-hydroxy-5-chloromethyl-1,2,4-triazole the products are, respectively:

N-[2-(1-benzyl-4-(1,2,3-triazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-(5-methyl-4-(1,2,3-triazolyl)methylamino)ethyl]guanidine

N-[2-(5-amino-4-(1,2,3-triazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-[2-(5hydroxy-4-(1,2,3-triazolyl)methylamino)ethyl]-N"-methylguanidine

4,5-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]-1,2,3-triazole

N-[2-(3-chloro-5-(1,2,4-triazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-[2-(3-hyroxy-5-(1,2,4-triazolyl)methylamino)ethyl]-N"-methylguanidine.

EXAMPLE 200

A mixture of 3-chloro-1,2,4-triazole (10.3 g., 0.1 m.) and1,3-diaminopropane (7.4 g, 0.1 m.) in ethanol containing sodium ethoxideis allowed to stand overnight. The solvent is removed to give3-(3-aminopropylamino)-1,2,4-triazole and this intermediate is reactedwith dimethyl-N-cyanoimidodithiocarbonate and methylamine by theprocedure of Example 3(d) to giveN-cyano-N'-methyl-N"-[3-(3-(1,2,4-triazolyl)amino)propyl]guanidine.

The by same procedure, using 4-chloro-5-methyl-1,2,3-triazole as thestarting material, the intermediate4-(3-aminopropylamino)-5-methyl-1,2,3-triazole and the productN-cyano-N'-methyl-N"-[3-(5-methyl-4-(1,2,3-triazolyl)amino)propyl]guanidineare prepared.

EXAMPLE 201

By the procedure of Example 18, 3-(3-aminopropylamino)-1,2,4-triazole isused as the starting material to giveN-cyano-N"-[3-(3-(1,2,4-triazolyl)amino)propyl]guanidine.

By the same procedure, using4-(3-aminopropylamino)-5-methyl-1,2,3-triazole, there is obtainedN-cyano-N'-[3-(5-methyl-4-(1,2,3-triazolyl)amino)propyl]guanidine.

EXAMPLE 202

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(3-(1,2,4-                                            triazolyl)methylamino)ethyl]guanidine                                                                   200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Similarly, a capsule is prepared using 200 mg. ofN-cyano-N'-methyl-N"-[2-(5-methyl-4-(1,2,3-triazolyl)methylamino)ethyl]guanidine.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a thiadiazole ring and Y is oxygen or sulphur(sulphur is preferred) are exemplified by the following examples.

EXAMPLE 203 2-(2-Amino-5-(1,3,4-thiadiazolyl)methylthio)ethylguanidinesulfate

By the procedure of Example 1, the following intermediate amine salt wasprepared: 2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazoledihydrobromide, m.p. 229°-232° C. By the procedure of Example 1converting this salt to the free base and then reacting withS-methylisothiouronium sulphate gives the title compound.

EXAMPLE 204

By the procedure of Example 20, using2-amino-5-mercapto-1,3,4-thiadiazole as the starting material, thefollowing intermediate dihydrobromide salt was prepared:2-amino-5-(3-aminopropylthio)-1,3,4-thiadiazole dihydrobromide, m.p.185°-188° C.

The above prepared dihydrobromide salt is converted to the free base andreacted with dimethyl-N-cyanoimidodithiocarbonate and then withmethylamine by the procedure of Example 3(c) to giveN-[3-(2-amino-5-(1,3,4-thiadizolyl)thio)propyl]-N'-cyano-N"-methylguanidine.Hydrolysis of this compound by the procedure of Example 3(e) givesN-[3-(2-amino-5(1,3,4-thiadiazolyl)-thio)propyl]-N'-methylguanidinedihydrochloride.

EXAMPLE 205

Reacting 5-chloro-3-chloromethyl-1,2,4-thiadiazole with cysteamine bythe procedure of Example 1(i)(c) gives3-[(2-aminoethyl)thiomethyl]-5-chloro-1,2,4-thiadiazole.

Using the above prepared intermediate in the procedure of Example 3givesN-[2-(5-chloro-3-(1,2,4-thiadiazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.

Reacting 3-[(2-aminoethyl)thiomethyl]-5-chloro-1,2,4-thiadiazole withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-[2-(5-chloro-3-(1,2,4-thiadiazolyl)methylthio)ethyl]-N'-nitroguanidine,and with N,S-dimethyl-N'-nitroisothiourea by the procedure of Example2(iii) givesN-[2-(5-chloro-3-(1,2,4-thiadiazolyl)methylthio)ethyl]-N'-methyl-N"-nitroguanidine.

EXAMPLE 206

Reacting 2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazole withS-methyl-N-nitroisothiourea by the procedure of Example 2 givesN-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)ethyl]-N'-nitroguanidine.Treatment with hydriodic acid gives the hydroiodide salt.

EXAMPLE 207N-Cyano-N'-methyl-N"-[3-(2-trifluoromethyl-5-(1,3,4-thiadiazolyl)thio)propyl]guandine

Using 2-trifluoromethyl-5-mercapto-1,3,4-thiadiazole as the startingmaterial in the procedure of Example 20, the title compound is prepared.

EXAMPLE 208N-Cyano-N'-methyl-N"-[3-(2-(1,3,4-thiadiazolyl)thio)propyl]guanidine

Using 2-mercapto-1,3,4-thiadiazole as the starting material in theprocedure of Example 20 gives the title compound.

EXAMPLE 209N-Cyano-N'-methyl-N"-[3-(3-(1,2,4-thiadiazolyl)thio)propyl]guanidine

Using 3-mercapto-1,2,4-thiadiazole as the starting material in theprocedure of Example 20 gives the title compound.

EXAMPLE 210

Reacting 4-hydroxymethyl-1,2,3-thiadiazole with cysteamine by theprocedure of Example 1 gives4-[(2-aminoethyl)thiomethyl]-1,2,3-thiadiazole. From this compound bythe procedures of Examples 1,2 and 3, the following products areprepared:

2-(4-(1,2,3-thiadiazolyl)methylthio)ethylguanidine guanidine sulphate

N-nitro-N'-[2-(4-(1,2,3-thiadiazolyl)methylthio)ethyl]guanidine

N-cyano-N'-methyl-N"-[2-(4-(1,2,3-thiadiazolyl)methylthio)ethyl]guanidine.

EXAMPLE 211

Converting 5-methyl-4-(1,2,3-thiadiazole)-carboxylic acid to the methylester and reducing the ester with lithium aluminium hydride intetrahydrofuran gives 4-hydroxymethyl-5-methyl-1,2,3-thiadiazole.

Reacting 4-hydroxymethyl-5-methyl-1,2,3-thiadiazole with cysteamine bythe procedure of Example 1 gives4-[(2-aminoethyl)thiomethyl]-5-methyl-1,2,3-thiadiazole.

Using the above prepared compound as the starting material in theprocedure of Example 3 givesN-cyano-N'-methyl-N"-[2-(5-methyl-4-(1,2,3-thiadiazolyl)methylthio)ethyl]guanidine.

By the same procedure using the following as starting materials(prepared from the corresponding carboxylic acids by the above processor, in the case of the 4-chloro substituted compound, by treatment withdiborane):

5-amino-4-hydroxymethyl-1,2,3-thiadiazole

4,5-di(hydroxymethyl)-1,2,3-thiadiazole

4-hydroxy-3-hydroxymethyl-1,2,5-thiadiazole p14-chloro-3-hydroxymethyl-1,2,5-thiadiazole the following products areobtained, respectively:

N-[2-(5-amino-4-(1,2,3-thiadiazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine

4,5-bis-[2-(N-cyano-N'-methylguanidino)ethylthiomethyl]-1,2,3-thiadiazole

N-cyano-N'-[2-(4-hydroxy-3-(1,2,5-thiadiazolyl)methylthio)ethyl]-N"-methylguanidine

N-[2-(4-chloro-3-(1,2,5-thiadiazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.

Also, reacting 4-hydroxymethyl-5-methyl-1,2,3-thiadiazole with3-mercaptopropylamine and using the resulting4-[(3-aminopropyl)thiomethyl]-5-methyl-1,2,3-thiadiazole as the startingmaterial in the procedure of Example 3 givesN-cyano-N'-methyl-N"-[3-(5-methyl-4-(1,2,3-thiadiazolyl)methylthio)propyl]guanidine.

EXAMPLE 212

N-[2-(2-Amino-5-(1,3,4-thiadiazolyl)ethyl)thioethyl]-N'-cyano-N"-methylguanidine

2-Amino-5(1,3,4-thiadiazole)acetic acid is converted to the methyl esterand the ester is reduced with lithium aluminum hydride intetrahydrofuran to give 2-amino-5-(2-hydroxyethyl)-1,3,4-thiadiazole.Treating with thionyl chloride gives2-amino-5-(2-chloroethyl)-1,3,4-thiadiazole. Using this compound as thestarting material in the procedure of Example 17 gives the titlecompound.

EXAMPLE 213N-Cyano-N'-methyl-N"-[3-(4-(1,2,3-thiadiazolyl)methoxy)propyl]guanidine

Treating 4-hydroxymethyl-1,2,3-thiadiazole with thionyl chloride andusing the resulting 4-chloromethyl-1,2,3-thiadiazole as the startingmaterial in the procedure of Example 22 gives the title compound.

EXAMPLE 214

Using 2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadizole as thestarting material in the procedure of Example 18 givesN-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)ethyl]-N'-cyanoguanidine.

EXAMPLE 215

Reaction of 2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazole withdimethyl-N-cyanoimidodithiocarbonate by the procedure of Example 3(c)(i)givesN-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)ethyl]-N'-cyano-S-methylisothiourea.

By the procedure of Example 3(c)(ii), the above prepared isothiourea isreacted with methylamine to giveN-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.

Reaction of the above prepared isothiourea with ethylamine by theprocedure of Example 4 givesN-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)ethyl]-N'-cyano-N"-ethylguanidine.

By the same procedure, using 2-(dimethylamino)ethylamine in place ofethylamine,N-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)ethyl]-N'-cyano-N"-(2-dimethylaminoethyl)guanidineis prepared.

EXAMPLE 216

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-[3-(2-Amino-5(1,3,4-thiadiazolyl)-                                          thiopropyl]-N'-cyano-N"-methylguanidine                                                                 150 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I whein A is such that there is formed togetherwith the carbon atom shown a thiadiazole ring and Y is NH areexemplified by the following examples.

EXAMPLE 217 2-(2-Amino-5-(1,3,4-thiadiazolyl)methylamino)ethylguanidinesulphate

By the procedure of Example 34, using2-amino-5-chloromethyl-1,3,4-thiadiazole, prepared by reacting thecorresponding 5-hydroxymethyl compound with thionyl chloride, as thestarting material, the title compound is prepared.

EXAMPLE 218

Reacting ethylenediamine with 2-amino-5-chloromethyl-1,3,4-thiadiazoleby the procedure of Example 34, then reacting the resultingN-[2-amino-5-(1,3,4-thiadiazolyl)methyl]ethylenediamine withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-[2-(2-amino-5-(1,3,4-thiadiazolyl)-methylamino)ethyl]-N'-nitroguanidine.Similarly, reaction ofN-[2-amino-5-(1,3,4-thiadiazolyl)methyl]ethylenediamine withN,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii)givesN-[2-(2-amino-5-(1,3,4-thiadiazolyl)amino)ethyl]-N'-methyl-N"-nitroguanidine.

EXAMPLE 219

Ethylenediamine is reacted with 2-amino-5-chloromethyl-1,3,4-thiadiazoleby the procedure of Example 34 and the resultingN-[2-amino-5-(1,3,4-thiadiazolyl)methyl]ethylenediamine is reacted withmethyl isothiocyanate by the procedure of Example 3(b) to give, afterchromatographing,N-methyl-N'-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylamino)ethyl]-thiourea.This thiourea is reacted with lead cyanamide by the procedure of Example3(b) to giveN-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.Acid hydrolysis of this compound by the procedure of Example 3(e) givesN-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylamino)ethyl]-N'-methylguanidinedihydrochloride.

EXAMPLE 220

Using ethyl isothiocyanate in place of methylisothiocyanate in theprocedure of Example 219 givesN-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylamino)ethyl]-N'-cyano-N"-ethylguanidine.

By the same procedure, using propyl isothiocyanate,N-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylamino)ethyl]-N'-cyano-N"-propylguanidineis prepared.

Similarly, using 2-dimethylaminoethyl isothiocyanate, the correspondingN"-(2-dimethylaminoethyl) compound is prepared.

EXAMPLE 221

Using, in the procedure of Example 219, the followingchloroalkylthiadiazoles (which may be prepared by treating thecorresponding hydroxyalkyl compounds with thionyl chloride):

5-chloro-3-chloromethyl-1,2,4-thiadiazole

4-chloromethyl-1,2,3-thiadiazole

3-chloromethyl-4-hydroxy-1,2,5-thiadiazole

4-chloromethyl-5-methyl-1,2,3-thiadiazole

2-amino-5-(2-chloroethyl)-1,3,4-thiadiazole

4,5-di(chloromethyl)-1,2,3-thiadiazole the following products areobtained, respectively:

N-[2-(5-chloro-3-(1,2,4-thiadiazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine

N-cyano-N'-methyl-N"-[2-(4-(1,2,3-thiadiazolyl)-methylamino)ethyl]guanidine

N-cyano-N"-[2-(4-hydroxy-3-(1,2,5-thiadiazolyl)-methylamino)ethyl]-N"-methylguanidine

N-cyano-N"-methyl-N"-[2-(5-methyl-4-(1,2,3-thiadiazolyl)methylamino)ethyl]guanidine

N-[2-(2-(2-amino-5-(1,3,4-thiadiazolyl)ethylamino)ethyl]-N'-cyano-N"-methylguanidine

4,5-bis-[2-(N-cyano-N'-methylguanidino)ethylaminomethyl]-1,2,3-thiadiazole.

Using, in the procedure of Example 219, 1,3-diaminopropane in place ofethylenediamine givesN-[3-(2-amino-5-(1,2,3-thiadiazolyl)methylamino)-propyl]-N'-cyano-N"-methylguanidine.

EXAMPLE 222

Using 2-amino-1,3,4-thiadiazole as the starting material in theprocedure of Example 3 gives 2-(3-aminopropylamino)-1,3,4-thiadiazole.

Using 2-(3-aminopropylamino)-1,3,4-thiadiazole as the starting materialin the procedure of Example 3 givesN-cyano-N'-methyl-N"-[3-(2-(1,3,4-thiadiazolyl)amino)propyl]guanidine.

EXAMPLE 223

Using 2-(3-aminopropylamine)-1,3,4-thiadiazole as the starting materialin the procedure of Example 18 givesN-cyano-N"-[3-(2-(1,3,4-thiadiazolyl)amino)propyl]guanidine.

EXAMPLE 224

Using the following compounds as starting materials in the procedure ofExample 200:

3-chloro-1,2,5-thiadiazole

2-bromo-5-trifluoromethyl-1,3,4-thiadiazole the following products areobtained, respectively:

N-cyano-N'-methyl-N"-[3-(3-(1,2,5-thiadiazolyl)amino)propyl]guanidine

N-cyano-N'-methyl-N"-[3-(5-trifluoromethyl-2-(1,3,4-thiadiazolyl)amino)propyl]guanidine.

Reaction of 3-amino-1,2,4-thiadiazole with 3-phthalimidopropyl bromideand hydrazinolysis of the product gives3-(3-aminopropylamino)-1,2,4-thiadiazole and from this intermediateN-cyano-N'-methyl-N"-[3-(3-(1,2,4-thiadiazolyl)amino)propyl]-guanidineis prepared.

EXAMPLE 225

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-[2-(2-Amino-5-(1,3,4-thiadiazolyl)-                                         methylamino)ethyl]-N'-cyano-N"-                                               methylguanidine           200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a benzimidazole ring and Y is oxygen orsulphur (sulphur is preferred) are exemplified by the followingexamples.

EXAMPLE 226 2-(2-Benzimidazolylmethylthio)guanidine sulphate

By the procedure of Example 1, the following intermediate amine salt wasprepared: 2-[(2-aminoethyl)-thiomethyl]benzimidazole, dihydrobromide,m.p. 242°-245° C. By the procedure of Example 1, converting this salt tothe free base and then reacting with S-methylisothiouronium sulphategives the title compound.

EXAMPLE 227

Reacting 2-[(2-aminoethyl)thiomethyl]benzimidazole withS-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-[2-(2-benzimidazolylmethylthio)ethyl]-N'-nitroguanidine. Treatmentwith hydrochloric acid gives the hydrochloride salt.

Similarly, reaction of the same starting material withN.S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii)givesN-[2-(2-benzimidazolylmethylthio)ethyl]-N'-methyl-N"-nitroguanidine.

EXAMPLE 228

Reacting 2-[(2-aminoethyl)thiomethyl]benzimidazole withdimethyl-N-cyanoimidodithiocarbonate by the procedure of Example 3(c)(i)givesN-cyano-N'-[2-(2-benzimidazolylmethylthio)ethyl]-S-methylisothiourea.Reacting this isothiourea compound with methylamine by the procedure ofExample 3(c)(ii) givesN-[2-(2-benzimidazolylmethylthio)ethyl]-N'-cyano-N"-methylguanidine.Hydrolysis of this compound by the procedure of Example 3(e) givesN-[2-(2-benzimidazolylmethylthio)ethyl]-N'-methylguanidinedihydrochloride.

EXAMPLE 229

ReactingN-cyano-N'-[2-(2-benzimidazolylmethylthio)ethyl]-S-methylisothioureawith ethylamine by the procedure of Example 4 givesN-[2-(2-benzimidazolylmethylthio)ethyl]-N'-cyano-N"-ethylguanidine.

Similarly, using propylamine in place of ethylamine, the correspondingN"-propyl compound is prepared.

Using 2-(dimethylamino)ethylamine in place of ethylamine gives thecorresponding N"-(2-dimethylaminoethyl) compound.

EXAMPLE 230N-[2-(2-(2-Benzimidazolyl)ethyl)thioethyl]-N'-cyano-N"-methylguanidine

Using 2-(2-chloroethyl)benzimidazole, prepared by treating2-(2-hydroxyethyl)benzimidazole with thionyl chloride, as the startingmaterial in the procedure of Example 17 gives the title compound.

EXAMPLE 231

Using 2-chloromethylbenzimidazole, prepared by reacting2-hydroxymethylbenzimidazole with thionyl chloride, as the startingmaterial in the procedure of Example 22 givesN-[3-(2-benzimidazolylmethoxy)-propyl]-N'-methylguanidine. Treatmentwith citric acid in ethanol gives the citrate salt.

EXAMPLE 232

By the procedure of Example 20 using 2-mercaptobenzimidazole as thestarting material,N-[3-(2-benzimidazolylthio)propyl]-N'-cyano-N"-methylguanidine isprepared.

EXAMPLE 233

Using 2-[(2-aminoethyl)thiomethyl]benzimidazole as the starting materialin the procedure of Example 18 givesN-[2-(2-benzimidazolylmethylthio)ethyl]-N'-cyanoguanidine.

EXAMPLE 234

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-[2-(2-Benzinidazolylmethylthio)-                                            ethyl]-N'-cyano-N"-methyl-                                                    guanidine                 150 mg.                                             Sucrose                   75 mg.                                              Starch                    25 mg.                                              Talc                      5 mg.                                               Stearic acid              2 mg.                                               ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a benzimidazole ring and Y is NH areexemplified by the following examples.

EXAMPLE 235 2-(2-Benzimidazolylamino)ethylguanidine sulphate

Using 2-chloromethylbenzimidazole as the starting material in theprocedure of Example 34, the title compound is prepared.

EXAMPLE 236

Reacting ethylenediamine with 2-chloromethylbenzimidazole by theprocedure of Example 34, then using the resultingN-(2-benzimidazolylmethyl)ethylenediamine as the starting material inthe procedures of Example 35 givesN-[2-(2-benzimidazolylmethylamino)ethyl]-N'-nitroguanidine andN-[2-(2-benzimidazolylmethylamino)ethyl]-N'-methyl-N"-nitroguanidine.

EXAMPLE 237

Reacting N-(2-benzimidazolylmethyl)ethylenediamine withN-cyano-N',S-dimethylisothiourea by the procedure of Example 36 givesN-[2-(2-benzimidazolylmethylamino)ethyl]-N'-cyano-N"-methylguanidine.Treating with hydrobromic acid gives the hydrobromide salt. Hydrolysisof this compound by the procedure of Example 3(e) givesN-[2-(2-benzmidazolylmethylamino)-ethyl-N'-methylguanidinetrihydrochloride.

EXAMPLE 238

Reacting N-(2-benzimidazolylmethyl)ethylenediamine with ethylisothiocyanate by the procedure of Example 3(b), then chromatographingand reacting the resulting thiourea with lead cyanamide by the procedureof Example 3(b) givesN-[2-(2-benzimidazolylmethylamino)-ethyl]-N'-cyano-N"-ethylguanidine.

Similarly, using the following isothiocyanates in place of ethylisothiocyanate:

propyl isothiocyanate

2-dimethylaminoethyl isothiocyanate the following products are obtained,respectively:

N-[2-(2-benzimidazolylmethylamino)ethyl]-N'-cyano-N"-propylguanidine

N-[2-(2-benzimidazolylmethylamino)ethyl]-N'-cyano-N"-(2-dimethylaminoethyl)guanidine.

Using in the above procedure,2-[(3-aminopropyl)aminomethyl]benzimidazole (prepared by reacting2-cyloromethylbenzimidazole with 1,3-diaminopropane) and methylisothiocyanate, the products isN-[3-(2-benzimidazolylmethylamino)propyl]-N'-cyano-N"-methylguanidine.

EXAMPLE 239

Using 2-aminobenzimidazole as the starting material in the procedure ofExample 40 gives 2-(3-aminopropylamino)benzimidazole as the intermediateand N-[3-(2-benzimdazolylamino)propyl]-N'-cyano-N"-methylguanidine asthe product.

EXAMPLE 240

Using 2-(3-aminopropylamino)benzimidazole as the starting material inthe procedure of Example 18 givesN-[3-(2-benzimidazolylamino)propyl]-N'-cyanoguanidine.

EXAMPLE 241N-[2-(2-(2-Benzimidazolyl)ethylamino)ethyl]-N'-cyano-N"-methylguanidine

Reacting 2-(2-chloroethyl)benzimidazole with ethylenediamine by theprocedure of Example 34, then reacting the resultingN-[2-(2-benzimidazolyl)ethyl]-ethylenediamine withN-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a) givesthe title compound.

EXAMPLE 242

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-[2-(2-Benzinidazolylmethylamino)-                                           ethyl]-N'-cyano-N"-methylguanidine                                                                      200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I where A is such that there is formed togetherwith the carbon atom shown a 5,6,7,8-tetrahydroimidazo[1,5-a]pyridinering and Y is oxygen or sulphur (sulphur is preferred) are exemplifiedby the following examples.

EXAMPLE 2432-[3-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridyl)methylthio]ethylguanidinesulphate

A solution of 1.58 molar n-butyl lithium in n-hexane (49 ml.) was addedover 0.5 hour to a stirred solution of5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (8.9 g.) in dry ether at -60°under nitrogen. After 3 hours, gaseous formaldehyde generated by thethermal condensation of paraformaldehyde (6.9 g.) was passed into thered solution. The mixture was allowed to warm to room temperatureovernight, acidified with hydrochloric acid and extracted withchloroform. The aqueous layer was basified with an excess of saturatedsodium carbonate solution and extracted with chloroform. Concentrationand recrystallisation of the residue from ethanolethyl acetate-petroleumether afforded 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine(7.7 g.) m.p. 188°-199°.

Reacting 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine withcysteamine hydrochloride by the procedure of Example 1 gives3-[(2-aminoethyl)thiomethyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.

Reacting the above prepared intermediate with S-methylisothiouroniumsulphate by the procedure of Example 1 gives the title compound.

EXAMPLE 244

Reacting3-[(2-aminoethyl)thiomethyl]-5,6,7,8-tetrahydroimidazo[1,5a]pyridinewith S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) givesN-nitro-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl[guanidine.Treating with hydrobromid acid gives the hydrobromide salt. Reaction ofthe same starting material with N,S-dimethyl-N'-nitroisothiourea by theprocedure of Example 2(iii) givesN-methyl-N'-nitro-N"-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl]guanidine.

EXAMPLE 245

Reacting3-[2-aminoethyl)thiomethyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridinewith dimethyl-N-cyanoimidothiocarbonate by the procedure of Example3(c)(i) givesN-cyano-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl)-S-methylisothiourea.

Reacting this isothiourea compound with methylamine by the procedure ofExample 3(c)(ii) givesN-cyano-N'-methyl-N"-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl[guanidine.Acid hydrolysis of this compound by the procedure of Example 3(e) givesN-methyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl]guanidinedihydrochloride.

EXAMPLE 246

ReactingN-cyano-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl]-S-methylisothioureawith ethylamine by the procedure of Example 4 givesN-cyano-N'-ethyl-N"-[2-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl]guanidine.

By the same procedure, using propylamine in place of ethylamine, thecorresponding N'-propyl compound is prepared.

Also, using 2-(dimethylamino)ethylamine, the correspondingN'-(2-dimethylaminoethyl) compound is prepared.

EXAMPLE 247N-Cyano-N'-methyl-N"-[3-(3-(5,6,7,8-tetrahydroimidazo-[1,5-a]pyridyl)methoxy)propyl]guanidine.

By the procedure of Example 22 using as the starting material3-chloromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, prepared bytreating the 3-hydroxymethyl compound with thionyl chloride, the titlecompound is prepared.

EXAMPLE 248

By the procedure of Example 18, using3-[(2-aminoethyl)thiomethyl]-5,6,7,8-tetrahydroimidazo-[1,5-a]pyridineas the starting material,N-cyano-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl[guanidineis prepared.

EXAMPLE 249

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(3-(5,6,7,8-                                          tetrahydroinidazol[1,5-a]pyridyl)-                                            methylthio)ethyl]guanidine                                                                              200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a 5,6,7,8-tetrahydroimidazo[1,5-a]pyridinering and Y is NH are exemplified by the following examples.

EXAMPLE 2502-[3-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridyl)methylamino]ethylguanidinesulphate

Using 3-chloromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, preparedby treating the corresponding hydroxymethyl compound with thionylchloride, as the starting material in the procedure of Example 34 givesthe title compound.

EXAMPLE 251

Reacting 5-chloromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine withethylenediamine by the procedure of Example 34 givesN-[3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methyl]ethylenediamine.Reacting this intermediate with S-methyl-N-nitroisothiourea by theprocedure of Example 2(ii) givesN-nitro-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylamino)ethyl]-guanidine.Treating with hydrochloric acid gives the hydrochloride salt.

Reaction of the above intermediate with N,S-dimethyl-N'-nitroisothioureaby the procedure of Example 2(iii) givesN-methyl-N'-nitro-N"-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylamino)ethyl]-guanidine.

EXAMPLE 252

Using 2-chloromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine as thestarting material in the procedure of Example 36 givesN-cyano-N'-methyl-N"-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylamino)ethyl]guanidine.Acid hydrolysis by the procedure of Example 3(e) givesN-methyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylamino)ethyl]guanidinetrihydrochloride.

EXAMPLE 253

ReactingN-[3-(5,6,7,8-tetrahydroimidazo-1,5-a]pyridyl)methyl]ethylenediaminewith ethyl isothiocyanate by the procedure of Example 3(b), thenchromatographing givesN-ethyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylamino)ethyl]thiourea.Reacting this thiourea compound with lead cyanamide by the procedure ofExample 3(b) givesN-cyano-N'-ethyl-N"-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylamino)ethyl]guanidine.

Using in place of ethyl isothiocyanate the following:

propyl isothiocyanate

2-dimethylaminoethyl isothiocyanate the following products are obtained,respectively:

N-cyano-N'-propyl-N"-[2-(3-(5,6,7,8-tetrahydroimidazo1,5-a]pyridyl)methylamino)ethyl]guanidine.

N-cyano-N'-dimethylaminoethyl)-N"-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylamino)ethyl]guanidine.

EXAMPLE 254

N-Cyano-N'-methyl-N"-[3-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylamino)propyl]-guanidine

Using as the starting materials in the procedure of Example 36,15-diaminopropane and3-chloromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]-pyridine, the titleproduct is prepared.

EXAMPLE 255

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Cyano-N'-methyl-N"-[2-(3-(5,6,7,8-                                          tetrahydroimidazo[1,5-a]pyridyl)-                                             methylamino)ethyl]guanidine                                                                             200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

The pharmaceutical compositions prepared as in foregoing examples areadministered to a subject within the dose ranges given hereinabove toinhibit H-2 histamine receptors.

In the foregoing examples, the temperatures are in degrees Centigrade.

What we claim is:
 1. A compound of the formula: ##STR15## wherein A issuch that there is formed together with the carbon atom shown anunsaturated heterocyclic nucleus, said unsaturated heterocyclic nucleusbeing a ring; X₁ is hydrogen, lower alkyl, hydroxyl, trifluoromethyl,benzyl, halogen, amino or ##STR16## X₂ is hydrogen or when X₁ is loweralkyl, lower alkyl or halogen, k is 0 to 2 and m is 2 or 3, providedthat the sum of k and m is 3 or 4; Y is oxygen, sulphur or NH; E is NR₂; R₁ is hydrogen, lower alkyl or di-lower alkylamino-lower alkyl; and R₂is hydrogen, nitro or cyano, or a pharmaceutically acceptable additionsalt thereof.
 2. A compound of claim 1 wheein Y is oxygen or sulphur. 3.A compound of claim 1 wherein Y is NH.
 4. A compound of claim 1 whereinsaid unsaturated heterocyclic nucleus is thiadiazole and R₂ is hydrogenor nitro.
 5. A compound of claim 4 wherein k is 1 and m is
 2. 6. Acompound of claim 1, said compound beingN-[2-(2-amino-5-1,3,4-thiadiazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.